Benzene, pyridine, and pyridazine derivatives

ABSTRACT

Disclosed are compounds and pharmaceutically acceptable salts of Formula I 
     
       
         
         
             
             
         
       
     
     wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , n, Q 1 , Q 2 , Q 3 , Y, and X 1 -X 4  are as defined herein. Compounds of Formula I are useful in the treatment of diseases and/or conditions related to cell proliferation, such as cancer, inflammation, arthritis, angiogenesis, or the like. Also disclosed are pharmaceutical compositions comprising compounds of the invention and methods of treating the aforementioned conditions using such compounds.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of Provisional Application No.60/656,230, filed Feb. 25, 2005, Provisional Application No. 60/705,715,filed Aug. 4, 2005, and Provisional Application No. 60/727,965, filedOct. 18, 2005.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The invention relates to benzene, pyridine, and pyridazine derivativesand more specifically to such compounds that are useful in the treatmentand/or prevention of diseases and/or conditions related to cellproliferation, such as cancer, inflammation and inflammation-associateddisorders, and conditions associated with angiogenesis. Compounds of theinvention are also useful in the treatment and/or prevention ofinfectious diseases, in particular, fungal infections.

2. Description of the Related Art

Cancer is characterized by abnormal cellular proliferation. Cancer cellsexhibit a number of properties that make them dangerous to the host,typically including an ability to invade other tissues and to inducecapillary ingrowth, which assures that the proliferating cancer cellshave an adequate supply of blood. A hallmark of cancerous cells is theirabnormal response to control mechanisms that regulate cell division innormal cells and continue to divide until they ultimately kill the host.

Angiogenesis is a highly regulated process under normal conditions,however many diseases are driven by persistent unregulated angiogenesis.Unregulated angiogenesis may either cause a particular disease directlyor exacerbate an existing pathological condition. For example, ocularneovascularization has not only been implicated as the most common causeof blindness, but also is believed the dominant cause of many eyediseases. Further, in certain existing conditions, for examplearthritis, newly formed capillary blood vessels invade the joints anddestroy cartilage, or in the case of diabetes, new capillaries formed inthe retina invade the vitreous, bleed, and cause blindness. Growth andmetastasis of solid tumors are also dependent on angiogenesis (Folkman,J., Cancer Research, 46, 467-473 (1986), Folkman, J., Journal of theNational Cancer Institute, 82, 4-6 (1989). It has been shown, forexample, that tumors which enlarge to greater than 2 mm must obtaintheir own blood supply and do so by inducing the growth of new capillaryblood vessels. Once these new blood vessels become embedded in thetumor, they provide a means for tumor cells to enter the circulation andmetastasize to distant sites such as liver, lung or bone (Weidner, N.,et al., The New England Journal of Medicine, 324(1), 1-8 (1991). Underconditions of unregulated angiogenesis, therapeutic methods designed tocontrol, repress, and/or inhibit angiogenesis could lead to theabrogation or mitigation of these conditions and diseases.

Inflammation is related to a variety of disorders such as pain,headaches, fever, arthritis, asthma, bronchitis, menstrual cramps,tendonitis, bursitis, psoriasis, eczema, burns, dermatitis, inflammatorybowel syndrome, Crohn's disease, gastritis, irritable bowel syndrome,ulcerative colitis, vascular diseases, Hodgkin's disease, sclerodoma,rheumatic fever, type I diabetes, myasthenia gravis, sarcoidosis,nephrotic syndrome, Behcet's syndrome, polymyositis, hypersensitivity,conjunctivitis, gingivitis, post-injury swelling, myocardial ischemia,and the like.

Heat-shock protein 90 (HSP-90) is a cellular chaperone protein requiredfor the activation of several eukaryotic protein kinases, including thecyclin-dependent kinase CDK4. Geldanamycin, an inhibitor of theprotein-refolding activity of HSP-90, has been shown to haveantiproliferative and antitumor activities.

HSP-90 is a molecular chaperone that guides the normal folding,intracellular disposition and proteolytic turnover of many keyregulators of cell growth and survival. Its function is subverted duringoncogenesis to make malignant transformation possible and to facilitaterapid somatic evolution, and to allow mutant proteins to retain or evengain function. Inhibition of HSP-90 will slow those process thus haspotential therapeutic use (Whitesell L, Lindquist, S L, Nature Rev.Cancer, 2005, 10, 761-72).

Ansamycin antibiotics, e.g., herbimycin A (HA), geldanamycin (GM), and17-allylaminogeldanamycin (17-AAG) are thought to exert theiranticancerous effects by tight binding of the N-terminus pocket ofHSP-90, thereby destabilizing substrates that normally interact withHSP-90 (Stebbins, C. et al. Cell 1997, 89, 239-250). This pocket ishighly conserved and has weak homology to the ATP-binding site of DNAgyrase (Stebbins, C. et al., supra; Grenert, J. P. et al. J. Biol. Chem.1997, 272, 23843-50).

In vitro and in vivo studies have demonstrated that occupancy of thisN-terminal pocket by ansamycins and other HSP-90 inhibitors altersHSP-90 function and inhibits protein folding. At high concentrations,ansamycins and other HSP-90 inhibitors have been shown to preventbinding of protein substrates to HSP-90 (Scheibel, T. H. et al. Proc.Natl. Acad. Sci. USA 1999, 96, 1297-302; Schulte, T. W. et al. J. Biol.Chem. 1995, 270, 24585-8; Whitesell, L., et al. Proc. Natl. Acad. Sci.USA 1994, 91, 8324-8328). Ansamycins have also been demonstrated toinhibit the ATP-dependent release of chaperone-associated proteinsubstrates (Schneider, C. L. et al. Proc. Natl. Acad. Sci., USA 1996,93, 14536-41; Sepp-Lorenzino et al. J. Biol. Chem. 1995, 270,16580-16587). In either event, the substrates are degraded by aubiquitin-dependent process in the proteasome (Schneider, C. L., supra;Sepp-Lorenzino, L., et al. J. Biol. Claim. 1995, 270, 16580-16587;Whitesell, L. et al. Proc. Natl. Acad. Sci. USA 1994, 91, 8324-8328).HSP-90 substrate destabilization occurs in tumor and non-transformedcells alike and has been shown to be especially effective on a subset ofsignaling regulators, e.g., Raf (Schulte, T. W. et al., Biochem.Biophys. Res. Commun. 1997, 239, 655-9 Schulte, T. W., et al., J. Biol.Chem. 1995, 270, 24585-8), nuclear steroid receptors (Segnitz, B.; U.Gehring J. Biol. Chem. 1997, 272, 18694-18701; Smith, D. F. et al. Mol.Cell. Biol. 1995, 15, 6804-12), v-Src (Whitesell, L. et al. Proc. Natl.Acad. Sci. USA 1994, 91, 8324-8328) and certain transmembrane tyrosinekinases (Sepp-Lorenzino, L. et al. J. Biol. Chez. 1995, 270,16580-16587) such as EGF receptor (EGFR) and HER2/Neu (Hartmann, F., etal. Int. J. Cancer 1997, 70, 221-9; Miller, P. et al. Cancer Res. 1994,54, 2724-2730; Mimnaugh, E. G., et al. J. Biol. Chem. 1996, 271,22796-801; Schnur, R. et al. J. Med. Chenu. 1995, 38, 3806-3812), CDK4,and mutant p53. Erlichman et al. Proc. AACR 2001, 42, abstract 4474. Theansamycin-induced loss of these proteins leads to the selectivedisruption of certain regulatory pathways and results in growth arrestat specific phases of the cell cycle (Muise-Heimericks, R. C. et al. J.Biol. Chez. 1998, 273, 29864-72), and apoptosis, and/or differentiationof cells so treated (Vasilevskaya, A. et al. Cancer Res., 1999, 59,3935-40). Inhibitors of HSP-90 thus hold great promise for the treatmentand/or prevention of many types of cancers and proliferative disorders,and also hold promise as traditional antibiotics.

Inhibition of HSP-90 is also known to result in up regulation of theexpression of the chaperone HSP70. HSP70 up regulation is considered tobe of therapeutic benefit for treatment of a wide range ofneurodegenerative diseases including, but not limited to: Alzheimer'sdisease; Parkinson's disease; Dementia with Lewy bodies; Amyotropiclateral sclerosis (ALS); Polyglutamine disease; Huntington's disease;Spinal and bulbar muscular atrophy (SBMA); and Spinocerebellar ataxias(SCA1-3,7). Therefore, the compounds described in the invention are ofpotential therapeutic use for treatment of such neurodegenerativediseases (Muchowski, P. J., Wacker J. L., Nat. Rev. Neurosci. 2005, 6,11-22.; Shen H. Y., et al. J. Biol. Chem. 2005, 280, 39962-9).

Inhibition of HSP-90 also has anti-fungal activity, both as a standalone therapy and in combination with standard anti-fungal therapiessuch as the azole class of drugs. Therefore, the compounds described inthe invention are of potential therapeutic use for treatment of fungalinfections including, but not limited to, life threatening systemicfungal infections (Cowen, L. E., Lindquist, S., Science 2005, 309,2185-9).

Inhibition of HSP-90 also has antimalarial activity; thus, inhibitors ofthis protein are useful as antimalarial drugs.

Therefore, there is a continuing need in the art for new methods oftreating cancer, inflammation and inflammation-associated disorders, andconditions or diseases related to uncontrolled angiogenesis.

SUMMARY OF THE INVENTION

In a broad aspect, the invention encompasses the compounds of formula Ishown below, pharmaceutical compositions containing those compounds andmethods employing such compounds or compositions in the treatment ofdiseases and/or conditions related to cell proliferation, such ascancer, inflammation, arthritis, angiogenesis, or the like.

The invention provides compounds of formula I,

or a pharmaceutically acceptable salt thereof, whereinR₃ and R₄ are independently

-   -   (a) H,    -   (b) halo, or    -   (c) a C₁-C₁₅ alkyl group where up to six of the carbon atoms in        said alkyl group are optionally replaced independently by R₂₂,        carbonyl, ethenyl, ethynyl or a moiety selected from N, O, S,        SO₂, or SO, with the proviso that two O atoms, two S atoms, or        an O and S atom are not immediately adjacent each other, wherein        -   R₂₂ is            -   (i) heteroaryl,            -   (ii) aryl,            -   (iii) saturated or unsaturated C₃-C₁₀ cycloalkyl, or            -   (iv) saturated or unsaturated C₂-C₁₀ heterocycloalkyl,                wherein            -   each aryl, heteroaryl, saturated or unsaturated                cycloalkyl, or saturated or unsaturated                heterocycloalkyl, independently, is optionally                substituted with at least one group, which independently                is hydroxy, halo, amino, cyano, carboxy, carboxamido,                nitro, oxo, —S—(C₁-C₆) alkyl, —SO₂—(C₁-C₆) alkyl,                —SO₂-aryl, —SO—(C₁-C₆)alkyl, —SO-aryl, —SO₂NH₂,                —SO₂NH—(C₁-C₆)alkyl, —SO₂NH-aryl, (C₁-C₆)alkoxy, or                mono- or di-(C₁-C₁₀)alkylamino; and        -   each R₂₂ is optionally fused to a C₆-C₁₀ aryl group, C₅-C₈            saturated cyclic group, or a C₅-C₁₀ heterocycloalkyl group;    -   wherein each (c) is optionally substituted at any available        position with C₁-C₁₀ alkyl, C₁-C₁₀ haloalkyl, C₂-C₁₀ alkenyl,        C₂-C₁₀ alkynyl, hydroxy, carboxy, carboxamido, oxo, halo, amino,        cyano, nitro, —SH, —S—(C₁-C₆)alkyl, —SO₂—(C₁-C₆) alkyl, —SO₂NH₂,        —SO₂NH—(C₁-C₆) alkyl, —SO₂NH-aryl, —SO₂-aryl, —SO—(C₁-C₆)alkyl,        —SO₂-aryl, C₁-C₆ alkoxy, C₂-C₁₀ alkenyloxy, C₂-C₁₀ alkynyloxy,        mono- or di-(C₁-C₁₀)alkylamino, —OC₁-C₁₀ alkyl-Z, or R₂₃,        wherein        -   Z is OR₀ or —N(R₃₀)₂, wherein            -   each R₃₀ is independently —H or C₁-C₆ alkyl, or N(R₃₀)₂                represents pyrrolidinyl, piperidinyl, piperazinyl,                azepanyl, 1,3- or 1,4-diazepanyl, or morpholinyl, each                of which is optionally substituted with hydroxy, amino,                aminoalkyl, C₁-C₆ alkyl, mono- or di(C₁-C₆)alkylamino,                C₁-C₆ alkoxy, or halogen;            -   R_(o) is —H, —C₁-C₁₀ alkyl, —C₂-C₁₀ alkenyl, —C₂-C₁₀                alkynyl, aryl, heteroaryl, or —C₁-C₆ acyl;        -   R₂₃ is            -   (1) heteroaryl,            -   (2) aryl,            -   (3) saturated or unsaturated C₅-C₁₀ cycloalkyl, or            -   (4) saturated or unsaturated C₅-C₁₀ heterocycloalkyl,                and        -   the R₂₃ groups are optionally substituted at least one group            which is independently hydroxy, oxo, halo, amino, cyano,            nitro, —SH, —S—(C₁-C₆)alkyl, —SO₂—(C₁-C₆)alkyl, —SO₂-aryl,            —SO—(C₁-C₆)alkyl, —SO-aryl, —SO₂NH₂, —SO₂NH—(C₁-C₆)alkyl,            —SO₂NH-aryl, (C₁-C₆)alkoxy, or mono- or            di-(C₁-C₁₀)alkylamino;    -   or R₃ and R₄ together with the atoms to which they are attached        form a 5-12 membered mono-, bi-, or tricyclic ring system fused        to the ring containing Q₁ and Q₂, where the 5-12 membered ring        is partially unsaturated or aromatic and optionally contains one        or two of oxygen, S(O)_(m) where m is 0, 1, or 2, nitrogen, or        NR₃₃ where R₃₃ is hydrogen or C₁-C₆ alkyl;    -   R₇ is O, S, NH, N—OH, N—NH₂, N—NHR₂₂, N—NH—(C₁-C₆ alkyl),        N—O—(C₀-C₆)alkyl-R₂₂, or N—(C₁-C₆ alkoxy optionally substituted        with carboxy);    -   Y is N or CR_(C), wherein        -   each R_(C) independently is hydrogen, halogen, cyano, nitro,            —C(O)R_(C′), C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl,            C₁-C₁₀ haloalkyl, C₃-C₇ cycloalkyl, C₃-C₇            cycloalkyl(C₁-C₁₀)alkyl, heterocycloalkyl, aryl, or            heteroaryl, wherein            -   each alkyl, aryl, cycloalkyl, heterocycloalkyl, and                heteroaryl group is optionally substituted with from 1-4                groups that are independently C₁-C₆ alkyl, C₁-C₆ alkoxy,                halogen, hydroxy, amino, mono- or di-(C₁-C₆)alkylamino,                cyano, nitro, halo(C₁-C₆)alkyl, halo(C₁-C₆)alkoxy,                carboxamide, heterocycloalkyl, aryl, or heteroaryl,                wherein                -   the aryl and heteroaryl groups are optionally                    substituted with from 1-4 groups that are                    independently C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen,                    hydroxy, amino, mono- or di-(C₁-C₆)alkylamino,                    halo(C₁-C₆)alkyl, or carboxamide;            -   R_(C′) is —C₁-C₆ alkyl, —OR_(C″), or —N(R_(CN))₂,                wherein R_(C″) is —H, C₁-C₁₀ alkyl, C₁-C₁₀ haloalkyl,                C₃-C₇ cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;                -   each R_(CN) is independently —H, C₁-C₁₀ alkyl,                    C₁-C₁₀ haloalkyl, C₃-C₇ cycloalkyl,                    heterocycloalkyl, C₁-C₆ acyl, aryl, or heteroaryl,                    wherein                -    each alkyl, cycloalkyl, heterocycloalkyl, aryl, and                    heteroaryl group is optionally substituted with from                    1-4 groups that are independently C₁-C₆ alkyl, C₁-C₆                    alkoxy, halogen, hydroxy, amino, mono- or                    di-(C₁-C₆)alkylamino, nitro, halo(C₁-C₆)alkyl,                    halo(C₁-C₆)alkoxy, or carboxamide;    -   X₁ is N or CR_(C);    -   Q₁, Q₂, and Q₃ are independently N or CR_(Q), wherein one and        only one of Q₁, Q₂, and Q₃ is C—R₂₁, and wherein        -   each R_(Q) is independently hydrogen, halogen, —N(R_(CN))₂,            C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₇ cycloalkyl, aryl, or            heteroaryl, or R₂₁, wherein        -   each alkyl, cycloalkyl, aryl, and heteroaryl group is            optionally substituted with from 1-4 groups that are            independently C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen, hydroxy,            amino, mono- or di-(C₁-C₆)alkylamino, halo(C₁-C₆)alkyl,            halo(C₁-C₆)alkoxy, or carboxamide;        -   R₂₁ is cyano, —C(O)OH, —C(O)—O(C₁-C₆alkyl), or a group of            the formula

-   -   -   -   R₁ and R₂ are independently H, hydroxy, C₁-C₆ alkyl,                C₂-C₆ alkenyl, C₂-C₆ alkynyl, heteroaryl, aryl, C₃-C₈                cycloalkyl, heterocycloalkyl, wherein                -   each alkyl, cycloalkyl, heterocycloalkyl, aryl, and                    heteroaryl group is optionally substituted with from                    1-4 groups that are independently C₁-C₆ alkyl, C₁-C₆                    alkoxy, halogen, hydroxy, amino, mono- or                    di-(C₁-C₆)alkylamino, nitro, halo(C₁-C₆)alkyl,                    halo(C₁-C₆) alkoxy, or carboxamide;

        -   or R₁ and R₂ together with the nitrogen to which they are            both attached, form a heterocycloalkyl which optionally            contains one or more additional heteroatoms which are,            independently, O, N, S, or N(R_(CN))

        -   and

        -   X₄ is O, S, NH, NOH, N—NH₂, N—NHaryl, N—NH—(C₁-C₆ alkyl), or            N—(C₁-C₆ alkoxy);            X₂ and X₃ are independently C, O, N, or S(O)_(p) wherein

p is 0, 1, or 2; and

n is 0, 1, 2, 3, or 4;provided that when

(i) X₂ is C, then

-   -   R₅ and R₆ are independently H, C₁-C₆ alkyl, or aryl, wherein the        aryl is optionally substituted with from 1-4 groups that are        independently C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen, hydroxy,        amino, mono- or di-(C₁-C₆) alkylamino, nitro, halo(C₁-C₆)alkyl,        halo(C₁-C₆)alkoxy, or carboxamide,    -   or wherein any two adjacent substituted aryl positions, together        with the carbon atoms to which they are attached, form an        unsaturated cycloalkyl or heterocycloalkyl; or    -   R₅ and R₆ together with the carbon to which they are attached        form a 3-8 membered ring;

(ii) X₂ is N, then

-   -   R₆ is absent and R₅ is H or C₁-C₆ alkyl;

(iii) X₃ is C, then

-   -   it is substituted with two groups that are independently H or        C₁-C₆ alkyl, or mono- or di-(C₁-C₆)alkylamino(C₁-C₆)alkyl; and

(iv) X₂ is O or S(O)_(p), then R₆ and R₅ are absent.

The invention also includes intermediates that are useful in making thecompounds of the invention.

The invention also provides pharmaceutical compositions comprising acompound or pharmaceutically acceptable salt of Formula I and at leastone pharmaceutically acceptable carrier, solvent, adjuvant or diluent.

The invention further provides methods of treating disease such ascancer, inflammation, arthritis, angiogenesis, and infection in apatient in need of such treatment, comprising administering to thepatient a compound or pharmaceutically acceptable salt of Formula I, ora pharmaceutical composition comprising a compound or salt of Formula I.

The invention also provides the use of a compound or salt according toFormula I for the manufacture of a medicament for use in treatingcancer, inflammation, arthritis, angiogenesis, or infection.

The invention also provides methods of preparing the compounds of theinvention and the intermediates used in those methods.

The invention also provides methods of treating a disease or conditionrelated to cell proliferation comprising administering a therapeuticallyeffective amount of a compound or salt of Formula I to a patient in needof such treatment.

The invention also provides methods of treating a disease or conditionrelated to cell proliferation comprising administering a therapeuticallyeffective amount of a compound or salt of Formula I to a patient in needof such treatment, where the disease of condition is cancer,inflammation, or arthritis.

The invention further provides methods of treating a subject sufferingfrom a disease or disorder of proteins that are either client proteinsfor HSP-90 or indirectly affect its client proteins, comprisingadministering to a subject in need of such treatment a therapeuticallyeffective amount of a compound or salt of Formula I.

The invention further provides methods of treating a subject sufferingfrom a disease or disorder of proteins that are either client proteinsfor HSP-90 or indirectly affect its client proteins, comprisingadministering to a subject in need of such treatment a therapeuticallyeffective amount of a compound or salt of Formula I, wherein the HSP-90mediated disorder is selected from the group of inflammatory diseases,infections, autoimmune disorders, stroke, ischemia, cardiac disorders,neurological disorders, fibrogenetic disorders, proliferative disorders,tumors, leukemias, neoplasms, cancers, carcinomas, metabolic diseasesand malignant disease.

The invention further provides methods of treating a subject sufferingfrom a fibrogenetic disorder of proteins that are either client proteinsfor HSP-90 or indirectly affect its client proteins, comprisingadministering to a subject in need of such treatment a therapeuticallyeffective amount of a compound or salt of Formula I, wherein thefibrogenetic disorder is selected from the group of scleroderma,polymyositis, systemic lupus, rheumatoid arthritis, liver cirrhosis,keloid formation, interstitial nephritis and pulmonary fibrosis.

The invention provides methods of protecting a subject from infectioncaused by an organism selected from Plasmodium species, preferablyPlasmodium falciparum. These methods comprising administering a compoundor salt of Formula I, preferably in an effective amount, to a subject atrisk of infection due to exposure to such organism.

The invention additionally provides methods of reducing the level ofinfection in a subject where the infection is caused by an organismselected from Plasmodium species, again preferably Plasmodiumfalciparum. These methods comprise administering to an infected subjectan effective amount of a compound or salt of Formula I.

The invention further provides methods for treating a patient infectedwith a metazoan parasite. These methods involve administering an amountof a compound of the invention effective to kill the parasite.

The invention further provides methods for treating a patient infectedwith a metazoan parasite wherein the parasite is Plasmodium falciparum.These methods involve administering an amount of a compound or salt ofthe invention effective to kill the parasite.

The invention further provides a compound or pharmaceutical compositionthereof in a kit with instructions for using the compound orcomposition.

The invention further provides compounds that may be administered aloneor in combination with other drugs or therapies known to be effective totreat the disease to enhance overall effectiveness of therapy.

The invention further provides methods for treating a fungal infectionin a patient in need of such treatment, comprising administering aneffective amount of a compound or salt of Formula I and an optionalanti-fungal agent or drug.

DETAILED DESCRIPTION OF THE INVENTION

In Formula I, R₃ and R₄ are, as noted above, independently (a) hydrogen,(b) halo, or (c) an alkyl group having from 1-15 carbon atoms. All, butno more than about six, of the carbon atoms in the alkyl group may bereplaced independently by the various groups listed above in connectionwith Formula I.

Thus, when the alkyl group is methyl, i.e., a one carbon atom alkylgroup, replacement of that carbon atom with, for example, nitrogen orsulfur, the resulting group will not be an alkyl group but instead willbe an amino or thio group, respectively. Similarly, when the carbon atombeing replaced terminates the alkyl group, the terminal group willbecome another moiety such as pyrimidinyl, amino, phenyl, or hydroxy.

Replacement of a carbon atom with a group such as, for example, oxygen,nitrogen, or sulfur will require appropriate adjustment of the number ofhydrogens or other atoms required to satisfy the replacing atom'svalency. Thus, when the replacement is N or O, the number of groupsattached to the atom being replaced will be reduced by one or two tosatisfy the valency of the nitrogen or oxygen respectively. Similarconsiderations will be readily apparent to those skilled in the art withrespect to replacement by ethenyl and ethynyl.

Thus, replacement as permitted herein results in the term “C₁-C₁₅ alkyl”as defined in connection with Formula I encompassing groups such as, butnot limited to:

-   -   amino, hydroxy, phenyl, benzyl, propylaminoethoxy,        butoxyethylamino, pyrid-2-ylpropyl, diethylaminomethyl,        pentylsulfonyl, methylsulfonamidoethyl,        3-[4-(butylpyrimidin-2-yl)ethyl]phenyl, butoxy, dimethylamino,        4-(2-(benzylamino)ethyl)pyridyl, but-2-enylamino,        4-(1-(methylamino)pent-3-en-2-ylthio)phenyl,        2-(N-methyl-hexanamido)ethoxy)methyl, and        4-(((3-methoxy-4-(4-methyl-1H-imidazol-2-yl)but-1-enyl)(methyl)amino)-methyl)phenyl.

Preferred compounds of Formula I include those where R₃ and R₄ areindependently hydrogen, halo, or —Z₁R_(Z1), wherein Z₁ is —O—, —NH—,—S(O)_(p)—, or —S(O)₂NH—, wherein p is 0, 1 or 2; and R_(Z1) is a C₁-C₁₄alkyl group where up to five of the carbon atoms in the alkyl group areoptionally replaced independently by R₂₂, carbonyl, ethenyl, ethynyl ora moiety selected from N, O, S, SO₂, or SO, with the proviso that two Oatoms, two S atoms, or an O and S atom are not immediately adjacent eachother,

-   -   wherein R_(Z1) is optionally substituted at any available        position with C₁-C₁₀ alkyl, C₁-C₁₀-haloalkyl, C₂-C₁₀ alkenyl,        C₂-C₁₀ alkynyl, hydroxy, carboxy, carboxamido, oxo, halo, amino,        cyano, nitro, —SH, —S—(C₁-C₆)alkyl, —SO₂—(C₁-C₆)alkyl, —SO₂NH₂,        —SO₂NH—(C₁-C₆)alkyl, —SO₂NH-aryl, —SO₂-aryl, —SO—(C₁-C₆)alkyl,        —SO₂-aryl, C₁-C₆ alkoxy, C₂-C₁₀ alkenyloxy, C₂-C₁₀ alkynyloxy,        mono- or di-(C₁-C₁₀)alkylamino, —OC₁-C₁₀ alkyl-Z, or R₂₃.

Even more preferred compounds of Formula I include those where R₃ and R₄are independently hydrogen, halo, or —Z₁R_(Z1), wherein Z₁ is —O— or—NH—; and R_(Z1) is a C₁-C₁₄ alkyl group where up to five of the carbonatoms in the alkyl group are optionally replaced independently by R₂₂,carbonyl, ethenyl, ethynyl or a moiety selected from N, O, S, SO₂, orSO, with the proviso that two O atoms, two S atoms, or an O and S atomare not immediately adjacent each other,

-   -   wherein R_(Z1) is optionally substituted at any available        position with C₁-C₁₀ alkyl, C₁-C₁₀ haloalkyl, C₂-C₁₀ alkenyl,        C₂-C₁₀ alkynyl, hydroxy, carboxy, carboxamido, oxo, halo, amino,        cyano, nitro, —SH, —S—(C₁-C₆)alkyl, —SO₂—(C₁-C₆)alkyl, —SO₂NH₂,        —SO₂NH—(C₁-C₆)alkyl, —SO₂NH-aryl, —SO₂-aryl, —SO—(C₁-C₆)alkyl,        —SO₂-aryl, C₁-C₆ alkoxy, C₂-C₁₀ alkenyloxy, C₂-C₁₀ alkynyloxy,        mono- or di-(C₁-C₁₀)alkylamino, —OC₁-C₁₀ alkyl-Z, or R₂₃.

Additional preferred compounds of Formula I include those where R₃ andR₄ are independently hydrogen, halo, or —N(H)R_(Z1), wherein R_(Z1) is aC₁-C₁₄ alkyl group where up to five of the carbon atoms in the alkylgroup are optionally replaced independently by R₂₂, carbonyl, ethenyl,ethynyl or a moiety selected from N, O, S, SO₂, or SO, with the provisothat two O atoms, two S atoms, or an O and S atom are not immediatelyadjacent each other,

-   -   wherein R_(Z1) is optionally substituted at any available        position with C₁-C₁₀ alkyl, C₁-C₁₀ haloalkyl, C₂-C₁₀ alkenyl,        C₂-C₁₀ alkynyl, hydroxy, carboxy, carboxamido, oxo, halo, amino,        cyano, nitro, —SH, —S—(C₁-C₆)alkyl, —SO₂—(C₁-C₆)alkyl, —SO₂NH₂,        —SO₂NH—(C₁-C₆)alkyl, —SO₂NH-aryl, —SO₂-aryl, —SO—(C₁-C₆)alkyl,        —SO₂-aryl, C₁-C₆ alkoxy, C₂-C₁₀ alkenyloxy, C₂-C₁₀ alkynyloxy,        mono- or di-(C₁-C₁₀)alkylamino, —OC₁-C₁₀ alkyl-Z, or R₂₃.

Most preferred compounds of Formula I include those where R₃ and R₄ areindependently hydrogen, halo, or —N(H)R_(Z1), wherein R_(Z1) is a C₁-C₁₄alkyl group where up to five of the carbon atoms in the alkyl group areoptionally replaced independently by R₂₂, carbonyl, ethenyl, ethynyl ora moiety selected from N, O, S, SO₂, or SO, with the proviso that two Oatoms, two S atoms, or an O and S atom are not immediately adjacent eachother,

-   -   wherein R_(Z1) is optionally substituted at any available        position with C₁-C₁₀ alkyl, C₁-C₁₀ haloalkyl, hydroxy, carboxy,        carboxamido, oxo, halo, amino, C₁-C₆ alkoxy, mono- or        di-(C₁-C₁₀)alkylamino, —OC₁-C₁₀ alkyl-Z, or R₂₃.

Additional preferred compounds of Formula I include those where R₃ andR₄ are independently hydrogen, halo, or —OR_(Z1), wherein R_(Z1) is aC₁-C₁₄ alkyl group where up to five of the carbon atoms in the alkylgroup are optionally replaced independently by R₂₂, carbonyl, ethenyl,ethynyl or a moiety selected from N, O, S, SO₂, or SO, with the provisothat two O atoms, two S atoms, or an O and S atom are not immediatelyadjacent each other,

-   -   wherein R_(Z1) is optionally substituted at any available        position with C₁-C₁₀ alkyl, C₁-C₁₀ haloalkyl, C₂-C₁₀ alkenyl,        C₂-C₁₀ alkynyl, hydroxy, carboxy, carboxamido, oxo, halo, amino,        cyano, nitro, —SH, —S—(C₁-C₆)alkyl, —SO₂—(C₁-C₆)alkyl, —SO₂NH₂,        —SO₂NH—(C₁-C₆)alkyl, —SO₂NH-aryl, —SO₂-aryl, —SO—(C₁-C₆)alkyl,        —SO₂-aryl, C₁-C₆ alkoxy, C₂-C₁₀ alkenyloxy, C₂-C₁₀ alkynyloxy,        mono- or di-(C₁-C₁₀)alkylamino, —OC₁-C₁₀ alkyl-Z, or R₂₃.

Most preferred compounds of Formula I include those where R₃ and R₄ areindependently hydrogen, halo, or —OR_(Z1), wherein R_(Z1) is a C₁-C₁₄alkyl group where up to five of the carbon atoms in the alkyl group areoptionally replaced independently by R₂₂, carbonyl, ethenyl, ethynyl ora moiety selected from N, O, S, SO₂, or SO, with the proviso that two Oatoms, two S atoms, or an O and S atom are not immediately adjacent eachother,

-   -   wherein R_(Z1) is optionally substituted at any available        position with C₁-C₁₀ alkyl, C₁-C₁₀ haloalkyl, hydroxy, carboxy,        carboxamido, oxo, halo, amino, C₁-C₆ alkoxy, mono- or        di-(C₁-C₁₀)alkylamino, —OC₁-C₁₀ alkyl-Z, or R₂₃.

Preferred compounds of Formula I include those where X₁ is carbonoptionally substituted with C₁-C₆ alkyl, more preferably C₁-C₃ alkyl.Other preferred compounds of Formula I are those where X₁ is carbonoptionally substituted with C₁-C₆ alkyl and Y is CR_(C) wherein R_(C) is—H, C₁-C₆ alkyl, C₁-C₃ haloalkyl, C₃-C₇ cycloalkyl, or C₃-C₇cycloalkyl(C₁-C₆)alkyl. More preferably, in compounds of Formula I, X₁is carbon optionally substituted with C₁-C₂ alkyl and Y is CR_(C)wherein R_(C) is —H, C₁-C₄ alkyl, C₁-C₃ haloalkyl, cyclopropyl, orcyclopropyl(C₁-C₂)alkyl.

Still more preferred compounds of Formula I are those where X₁ is CH.Other more preferred compounds of Formula I are those where X₁ is CH andY is CR_(C) wherein R_(C) is —H, C₁-C₃ alkyl, C₁-C₃ haloalkyl, C₃-C₅cycloalkyl, or C₃-C₅ cycloalkyl(C₁-C₂)alkyl. Even more preferredcompounds of Formula I are those where X₁ is CH and Y is CR_(C) whereinR_(C) is —H, methyl, ethyl, trifluoromethyl, cyclopropyl, orcyclopropylmethyl. Particularly preferred compounds of Formula I arethose where X₁ is CH and, Y is CR_(C) wherein R_(C) is methyl, ethyl, orcyclopropyl. Other particularly preferred compounds of Formula I arethose where X₁ is CH and Y is CR_(C) wherein R_(C) is trifluoromethyl.Other particularly preferred compounds of Formula I are those where X₁is CH and Y is CR_(C) wherein R_(C) is methyl. Other particularlypreferred compounds of Formula I are those where X₁ is CH and Y isCR_(C) wherein R_(C) is ethyl. Other particularly preferred compounds ofFormula I are those where X₁ is CH and Y is CR_(C) wherein R_(C) iscyclopropyl.

Still other preferred compounds of formula I are those where X₁ is CH, Yis CR_(C) wherein R_(C) is —H, C₁-C₃ alkyl, C₁-C₃ haloalkyl, or C₃-C₇cycloalkyl, and R₃ is amino or C₁-C₃ alkylamino substituted on the aminoor the alkyl with an optionally substituted aryl, optionally substitutedheterocycloalkyl, or optionally substituted cycloalkyl group. Preferredsubstituents on these cyclic groups are hydroxy, C₁-C₃ alkoxy, oxo,halo, C₁-C₃ alkyl, amino, mono- or di-C₁-C₃alkylamino, and nitro. Morepreferably the optional substituents on these cyclic groups are hydroxy,C₁-C₃alkoxy, and oxo. These cyclic groups are optionally substitutedwith from 1-4, preferably 1-3 of these substituents.

Still more preferred compounds of Formula I are those where X₁ is N.Other more preferred compounds of Formula I are those where X₁ is N andY is CR_(C) wherein R_(C) is —H, C₁-C₃ alkyl, C₁-C₃ haloalkyl, C₃-C₅cycloalkyl, or C₃-C₅ cycloalkyl(C₁-C₂)alkyl. Even more preferredcompounds of Formula I are those where X₁ is N and Y is CR_(C) whereinR_(C) is —H, methyl, ethyl, trifluoromethyl, cyclopropyl, orcyclopropylmethyl. Particularly preferred compounds of Formula I arethose where X₁ is N and Y is CR_(C) wherein R_(C) is methyl, ethyl, orcyclopropyl. Other particularly preferred compounds of Formula I arethose where X₁ is N and Y is CR_(C) wherein R_(C) is trifluoromethyl.Other particularly preferred compounds of Formula I are those where X₁is N and Y is CR_(C) wherein R_(C) is methyl. Other particularlypreferred compounds of Formula I are those where X₁ is N and Y is CR_(C)wherein R_(C) is ethyl. Other particularly preferred compounds ofFormula I are those where X₁ is N and Y is CR_(C) wherein R_(C) iscyclopropyl.

Still other preferred compounds of formula I are those where X₁ is N, Yis CR_(C) wherein R_(C) is —H, C₁-C₃ alkyl, C₁-C₃ haloalkyl, or C₃-C₇cycloalkyl and R₃ is amino or C₁-C₃ alkylamino substituted on the aminoor the alkyl with an optionally substituted aryl, optionally substitutedheterocycloalkyl, or optionally substituted cycloalkyl group. Preferredsubstituents on these cyclic groups are hydroxy, C₁-C₃alkoxy, oxo, halo,C₁-C₃alkyl, amino, mono- or di-C₁-C₃alkylamino, and nitro. Morepreferably the optional substituents on these cyclic groups are hydroxy,C₁-C₃alkoxy, and oxo. These cyclic groups are optionally substitutedwith from 1-4, preferably 1-3 of these substituents.

Other preferred compounds of Formula I are those where Q₃ is CR₂₁,wherein

R₂₁ is a group of the formula,

R₇ is O; and

Y is CR_(C), wherein R_(C) is hydrogen, C₁-C₃ alkyl, C₃-C₅ cycloalkyl,trifluoromethyl, or C₃-C₅ cycloalkyl(C₁-C₂)alkyl. Such compounds arecompounds of Formula II herein.

Other preferred compounds of Formula II are those where, R₃ and R₄ are,as noted above, independently (a) hydrogen, (b) halo, or (c) an alkylgroup having from 1-15 carbon atoms. All, but no more than about six, ofthe carbon atoms in the alkyl group may be replaced independently by thevarious groups listed above in connection with Formula I.

Other preferred compounds of Formula I are those where Q₃ is CR₂₁,wherein

R₂₁ is a group of the formula,

andX₃ is C substituted with R_(9a) and R_(9b), wherein R_(9a) and R_(9b)are independently H or C₁-C₆ alkyl.Such compounds are hereinafter compounds of Formula III.

Other preferred compounds of Formula I are those where Q₃ is CR₂₁,wherein

R₂₁ is a group of the formula,

andQ₁ and Q₂ are independently C substituted with R_(10a) and R_(10b)respectively, wherein R_(10a) and R_(10b) are independently H or C₁-C₆alkyl. Such compounds are hereinafter compounds of Formula IV.

Other preferred compounds of Formula I are those where Q₃ is CR₂₁,wherein

R₂₁ is a group of the formula,

and

-   -   X₁ is C substituted with R₁₁ where R₁₁ hydrogen, halogen, cyano,        nitro, —C(O)R_(C′), C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀        alkynyl, C₁-C₁₀ haloalkyl, C₃-C₇ cycloalkyl, C₃-C₇        cycloalkyl(C₁-C₁₀)alkyl, heterocycloalkyl, aryl, or heteroaryl,        wherein        -   R_(C′) is —C₁-C₆ alkyl, —OR_(C″), or —N(R_(CN))₂, wherein            -   R_(C″) is —H, C₁-C₁₀ alkyl, C₁-C₁₀ haloalkyl, C₃-C₇                cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;                each R_(CN) is independently —H, —C₁-C₁₀ alkyl,                —C₁-C₁₀-haloalkyl, —C₃-C₇ cycloalkyl, -heterocycloalkyl,                —C₁-C₆ acyl, -aryl, or -heteroaryl. Such compounds are                hereinafter compounds of Formula V.

Preferred compounds of Formula V are those where R₁₁ is hydrogen,halogen, C₁-C₁₀ alkyl, C₁-C₁₀ haloalkyl, C₃-C₇ cycloalkyl, C₃-C₇cycloalkyl(C₁-C₁₀)alkyl, aryl, or heteroaryl.

More preferred compounds of Formula V are those where R₁₁ is H or C₁-C₆alkyl.

Other preferred compounds of Formula I are those where Q₃ is CR₂₁,wherein

R₂₁ is a group of the formula,

andX₁ is N. Such compounds are hereinafter compounds of Formula Va.

Other preferred compounds of Formula I are those where Q₃ is CR₂₁,wherein

R₂₁ is a group of the formula,

andX₂ is C substituted with R₅ and R₆, wherein R₅ and R₆ are independentlyH or C₁-C₄ alkyl. Such compounds are hereinafter compounds of FormulaVI.

Preferred compounds of any of Formulas I-VI include compounds where R₃and R₄ are independently hydrogen, halo, or —Z₁R_(Z1), wherein Z₁ is —O—or —NH—; and R_(Z1) is a C₁-C₁₄ alkyl group where up to five of thecarbon atoms in the alkyl group are optionally replaced independently byR₂₂, carbonyl, ethenyl, ethynyl or a moiety selected from N, O, S, SO₂,or SO, with the proviso that two O atoms, two S atoms, or an O and Satom are not immediately adjacent each other,

-   -   wherein R_(Z1) is optionally substituted at any available        position with C₁-C₁₀ alkyl, C₁-C₁₀ haloalkyl, C₂-C₁₀ alkenyl,        C₂-C₁₀ alkynyl, hydroxy, carboxy, carboxamido, oxo, halo, amino,        cyano, nitro, —SH, —S—(C₁-C₆)alkyl, —SO₂—(C₁-C₆)alkyl, —SO₂NH₂,        —SO₂NH—(C₁-C₆)alkyl, —SO₂NH-aryl, —SO₂-aryl, —SO—(C₁-C₆)alkyl,        —SO₂-aryl, C₁-C₆ alkoxy, C₂-C₁₀ alkenyloxy, C₂-C₁₀ alkynyloxy,        mono- or di-(C₁-C₁₀)alkylamino, —OC₁-C₁₀ alkyl-Z, or R₂₃.

More preferred compounds of the invention are those of Formulas I-VIwhere R₃ and R₄ are independently hydrogen, halo, or —N(H)R_(Z1),wherein R_(Z1) is a C₁-C₁₄ alkyl group where up to five of the carbonatoms in the alkyl group are optionally replaced independently by R₂₂,carbonyl, ethenyl, ethynyl or a moiety selected from N, O, S, SO₂, orSO, with the proviso that two O atoms, two S atoms, or an O and S atomare not immediately adjacent each other,

-   -   wherein R_(Z1) is optionally substituted at any available        position with C₁-C₁₀ alkyl, C₁-C₁₀ haloalkyl, C₂-C₁₀ alkenyl,        C₂-C₁₀ alkynyl, hydroxy, carboxy, carboxamido, oxo, halo, amino,        cyano, nitro, —SH, —S—(C₁-C₆)alkyl, —SO₂—(C₁-C₆)alkyl, —SO₂NH₂,        —SO₂NH—(C₁-C₆)alkyl, —SO₂NH-aryl, —SO₂-aryl, —SO—(C₁-C₆)alkyl,        —SO₂-aryl, C₁-C₆ alkoxy, C₂-C₁₀ alkenyloxy, C₂-C₁₀ alkynyloxy,        mono- or di-(C₁-C₁₀)alkylamino, —OC₁-C₁₀ alkyl-Z, or R₂₃.

More preferred compounds of the invention are those of Formulas I-VIwhere R₄ is H, C₁-C₄ alkyl or halogen.

Preferred compounds of Formulas II-VI include those where X₁ is carbonoptionally substituted with C₁-C₃ alkyl (preferably methyl) and Y isCR_(C) wherein R_(C) is C₁-C₂ alkyl, trifluoromethyl, cyclopropyl, orcyclopropyl(C₁-C₂)alkyl. More preferably in compounds of Formulas II-VI,X₁ is CH and Y is CR_(C) wherein R_(C) is C₁-C₂ alkyl (preferablymethyl).

More preferred compounds of the invention are those of Formula I whereinQ₃ is CR₂₁, wherein

R₂₁ is a group of the formula,

X₂ is C substituted with two groups that are independently H or C₁-C₄alkyl;X₁ is C substituted with H or C₁-C₆ alkyl;Q₁ and Q₂ are independently C substituted with H or C₁-C₆ alkyl;

R₇ is O;

Y is CR_(C), wherein

R_(C) is —H, methyl, ethyl, trifluoromethyl, or cyclopropyl; R₃ and R₄are independently hydrogen, halo, or —Z₁R_(Z1), wherein Z₁ is —O—, —NH—,—S(O)_(p)—, or —S(O)₂NH—, wherein p is 0, 1 or 2; and R_(Z1) is a C₁-C₁₄alkyl group where up to five of the carbon atoms in the alkyl group areoptionally replaced independently by R₂₂, carbonyl, ethenyl, ethynyl ora moiety selected from N, O, S, SO₂, or SO, with the proviso that two Oatoms, two S atoms, or an O and S atom are not immediately adjacent eachother,

-   -   wherein R_(Z1) is optionally substituted at any available        position with C₁-C₁₀ alkyl, C₁-C₁₀ haloalkyl, C₂-C₁₀ alkenyl,        C₂-C₁₀ alkynyl, hydroxy, carboxy, carboxamido, oxo, halo, amino,        cyano, nitro, —SH, —S—(C₁-C₆)alkyl, —SO₂—(C₁-C₆)alkyl, —SO₂NH₂,        —SO₂NH—(C₁-C₆)alkyl, —SO₂NH-aryl, —SO₂-aryl, —SO—(C₁-C₆)alkyl,        —SO₂-aryl, C₁-C₆ alkoxy, C₂-C₁₀ alkenyloxy, C₂-C₁₀ alkynyloxy,        mono- or di-(C₁-C₁₀)alkylamino, —OC₁-C₁₀ alkyl-Z, or R₂₃; and        n is 1 or 2.

More preferred compounds of the invention are those of Formula I wherein

R₁ and R₂ are independently H or C₁-C₄ alkyl;Q₁ and Q₂ are both CH;X₂ is C substituted with two independently selected C₁-C₄ alkyl groups;andn is 1.

Other preferred compounds of the invention include those having theformula VII,

wherein X₁ and R_(C) are as defined in Formula I;R₅ and R₆ are independently H or C₁-C₄ alkyl;R₁₁ is H or C₁-C₆ alkyl;R_(10a) and R_(10b) are independently H or C₁-C₆ alkyl;R_(9a) and R_(9b) are independently H or C₁-C₆ alkyl;R₃ and R₄ are independently hydrogen, halo, or —Z₁R_(Z1), whereinZ₁ is —O—, —NH—, —S(O)_(p)—, or —S(O)₂NH—, wherein p is 0, 1 or 2; andR_(Z1) is a C₁-C₁₄ alkyl group where up to five of the carbon atoms inthe alkyl group are optionally-replaced independently by R₂₂, carbonyl,ethenyl, ethynyl or a moiety selected from N, O, S, SO₂, or SO, with theproviso that two O atoms, two S atoms, or an O and S atom are notimmediately adjacent each other,

-   -   wherein R_(Z1) is optionally substituted at any available        position with C₁-C₁₀ alkyl, C₁-C₁₀ haloalkyl, C₂-C₁₀ alkenyl,        C₂-C₁₀ alkynyl, hydroxy, carboxy, carboxamido, oxo, halo, amino,        cyano, nitro, —SH, —S—(C₁-C₆)alkyl, —SO₂—(C₁-C₆)alkyl, —SO₂NH₂,        —SO₂NH—(C₁-C₆)alkyl, —SO₂NH-aryl, —SO₂-aryl, —SO—(C₁-C₆)alkyl,        —SO₂-aryl, C₁-C₆ alkoxy, C₂-C₁₀ alkenyloxy, C₂-C₁₀ alkynyloxy,        mono- or di-(C₁-C₁₀)alkylamino, —OC₁-C₁₀ alkyl-Z, or R₂₃; and        n is 1 or 2.

Preferred compounds of Formula VII include those where R₁ and R₂ areindependently H or C₁-C₄ alkyl;

R_(10a) and R_(10b) are both H; andR₅ and R₆ are independently C₁-C₄ alkyl.

Other preferred compounds of Formula VII include those

where

X₁ is N.

Other preferred compounds of Formula VII include those where X₁ isCR_(C), wherein R_(C) is hydrogen, methyl, ethyl, cyclopropyl,cyclopropylmethyl, fluoromethyl, difluoromethyl, or trifluoromethyl. Ina preferred embodiment of this aspect, the R_(C) group derived from X₁is hydrogen, methyl, or trifluoromethyl, and the R_(C) group derivedfrom Y carries the definition given in connection with Formula I.

Other preferred compounds of Formula I include those of formula VIII,

wherein R_(C) is H, C₁-C₆ alkyl, trifluoromethyl, or cyclopropyl; andR₁-R₆, X₁, and X₄ carry the same definitions as for Formula I.

Preferred compounds of Formula VIII include those where X₁ is N.

Preferred compounds of Formula VIII include those where X₁ is CR_(C),wherein R_(C) is hydrogen, methyl, ethyl, cyclopropyl,cyclopropylmethyl, fluoromethyl, difluoromethyl, or trifluoromethyl. Ina preferred embodiment of this aspect, the R_(C) group derived from X₁is hydrogen, methyl, or trifluoromethyl, and the R_(C) group derivedfrom Y carries the definition given in connection with Formula I.

Preferred compounds of Formula VIII include those where R₃ and R₄ areindependently hydrogen, halo, or —Z₁R_(Z1), wherein Z₁ is —O—, —NH—,—S(O)_(p)—, or —S(O)₂NH—, wherein p is 0, 1 or 2; and R_(Z1) is a C₁-C₁₄alkyl group where up to five of the carbon atoms in the alkyl group areoptionally replaced independently by R₂₂, carbonyl, ethenyl, ethynyl ora moiety selected from N, O, S, SO₂, or SO, with the proviso that two Oatoms, two S atoms, or an O and S atom are not immediately adjacent eachother,

-   -   wherein R_(Z1) is optionally substituted at any available        position with C₁-C₁₀ alkyl, C₁-C₁₀ haloalkyl, C₂-C₁₀ alkenyl,        C₂-C₁₀ alkynyl, hydroxy, carboxy, carboxamido, oxo, halo, amino,        cyano, nitro, —SH, —S—(C₁-C₆)alkyl, —SO₂—(C₁-C₆)alkyl, —SO₂NH₂,        —SO₂NH—(C₁-C₆)alkyl, —SO₂NH-aryl, —SO₂-aryl, —SO—(C₁-C₆)alkyl,        —SO₂-aryl, C₁-C₆ alkoxy, C₂-C₁₀ alkenyloxy, C₂-C₁₀ alkynyloxy,        mono- or di-(C₁-C₁₀)alkylamino, —OC₁-C₁₀ alkyl-Z, or R₂₃.

Preferred compounds of Formula VIII include those where R₃ and R₄ areindependently hydrogen, halo, or —Z₁R_(Z1), wherein Z₁ is —O—, —NH—,—S(O)_(p)—, or —S(O)₂NH—, wherein p is 0, 1 or 2; and R_(Z1) is a C₁-C₁₄alkyl group where up to five of the carbon atoms in the alkyl group areoptionally replaced independently by R₂₂, carbonyl, ethenyl, ethynyl ora moiety selected from N, O, S, SO₂, or SO, with the proviso that two Oatoms, two S atoms, or an O and S atom are not immediately adjacent eachother,

-   -   wherein R_(Z1) is optionally substituted at any available        position with C₁-C₁₀ alkyl, C₁-C₁₀ haloalkyl, C₂-C₁₀ alkenyl,        C₂-C₁₀ alkynyl, hydroxy, carboxy, carboxamido, oxo, halo, amino,        cyano, nitro, —SH, —S—(C₁-C₆)alkyl, —SO₂—(C₁-C₆)alkyl, —SO₂NH₂,        —SO₂NH—(C₁-C₆)alkyl, —SO₂NH-aryl, —SO₂-aryl, —SO—(C₁-C₆)alkyl,        —SO₂-aryl, C₁-C₆ alkoxy, C₂-C₁₀alkenyloxy, C₂-C₁₀ alkynyloxy,        mono- or di-(C₁-C₁₀)alkylamino, —OC₁-C₁₀ alkyl-Z, or R₂₃; and

X₄ is O.

Preferred compounds of Formula VIII include those where R₃ and R₄ areindependently hydrogen, halo, or —Z₁R_(Z1), wherein Z₁ is —O—, —NH—,—S(O)_(p)—, or —S(O)₂NH—, wherein p is 0, 1 or 2; and R_(Z1) is a C₁-C₁₄alkyl group where up to five of the carbon atoms in the alkyl group areoptionally replaced independently by R₂₂, carbonyl, ethenyl, ethynyl ora moiety selected from N, O, S, SO₂, or SO, with the proviso that two Oatoms, two S atoms, or an O and S atom are not immediately adjacent eachother,

-   -   wherein R_(Z1) is optionally substituted at any available        position with C₁-C₁₀ alkyl, C₁-C₁₀ haloalkyl, C₂-C₁₀ alkenyl,        C₂-C₁₀ alkynyl, hydroxy, carboxy, carboxamido, oxo, halo, amino,        cyano, nitro, —SH, —S—(C₁-C₆)alkyl, —SO₂—(C₁-C₆)alkyl, —SO₂NH₂,        —SO₂NH—(C₁-C₆)alkyl, —SO₂NH-aryl, —SO₂-aryl, —SO—(C₁-C₆)alkyl,        —SO₂-aryl, C₁-C₆ alkoxy, C₂-C₁₀ alkenyloxy, C₂-C₁₀ alkynyloxy,        mono- or di-(C₁-C₁₀)alkylamino, —OC₁-C₁₀ alkyl-Z, or R₂₃; and

X₄ is N—OH.

Other preferred compounds of Formula VIII include those where R₃ and R₄are independently hydrogen, halo, or —Z₁R_(Z1), wherein Z₁ is —O— or—NH—; and R_(Z1) is a C₁-C₁₄ alkyl group where up to five of the carbonatoms in the alkyl group are optionally replaced independently by R₂₂,carbonyl, ethenyl, ethynyl or a moiety selected from N, O, S, SO₂, orSO, with the proviso that two O atoms, two S atoms, or an O and S atomare not immediately adjacent each other,

-   -   wherein R_(Z1) is optionally substituted at any available        position with C₁-C₁₀ alkyl, C₁-C₁₀ haloalkyl, C₂-C₁₀ alkenyl,        C₂-C₁₀ alkynyl, hydroxy, carboxy, carboxamido, oxo, halo, amino,        cyano, nitro, —SH, —S—(C₁-C₆)alkyl, —SO₂—(C₁-C₆)alkyl, —SO₂NH₂,        —SO₂NH—(C₁-C₆)alkyl, —SO₂NH-aryl, —SO₂-aryl, —SO—(C₁-C₆)alkyl,        —SO₂-aryl, C₁-C₆ alkoxy, C₂-C₁₀ alkenyloxy, C₂-C₁₀ alkynyloxy,        mono- or di-(C₁-C₁₀)alkylamino, —OC₁-C₁₀ alkyl-Z, or R₂₃.

Other preferred compounds of Formula VIII include those where R₃ and R₄are independently hydrogen, halo, or —Z₁R_(Z1), wherein Z₁ is —O— or—NH—; and R_(Z1) is a C₁-C₁₄ alkyl group where up to five of the carbonatoms in the alkyl group are optionally replaced independently by R₂₂,carbonyl, ethenyl, ethynyl or a moiety selected from N, O, S, SO₂, orSO, with the proviso that two O atoms, two S atoms, or an O and S atomare not immediately adjacent each other,

-   -   wherein R_(Z1) is optionally substituted at any available        position with C₁-C₁₀ alkyl, C₁-C₁₀ haloalkyl, C₂-C₁₀ alkenyl,        C₂-C₁₀ alkynyl, hydroxy, carboxy, carboxamido, oxo, halo, amino,        cyano, nitro, —SH, —S—(C₁-C₆)alkyl, —SO₂—(C₁-C₆)alkyl, —SO₂NH₂,        —SO₂NH—(C₁-C₆)alkyl, —SO₂NH-aryl, —SO₂-aryl, —SO—(C₁-C₆)alkyl,        —SO₂-aryl, C₁-C₆ alkoxy, C₂-C₁₀ alkenyloxy, C₂-C₁₀ alkynyloxy,        mono- or di-(C₁-C₁₀)alkylamino, —OC₁-C₁₀ alkyl-Z, or R₂₃; and

X₄ is o.

Other preferred compounds of Formula VIII include those where R₃ and R₄are independently hydrogen, halo, or —Z₁R_(z1), wherein Z₁ is —O— or—NH—; and R_(Z1) is a C₁-C₁₄ alkyl group where up to five of the carbonatoms in the alkyl group are optionally replaced independently by R₂₂,carbonyl, ethenyl, ethynyl or a moiety selected from N, O, S, SO₂, orSO, with the proviso that two O atoms, two S atoms, or an O and S atomare not immediately adjacent each other,

-   -   wherein R_(Z1) is optionally substituted at any available        position with C₁-C₁₀ alkyl, C₁-C₁₀ haloalkyl, C₂-C₁₀ alkenyl,        C₂-C₁₀ alkynyl, hydroxy, carboxy, carboxamido, oxo, halo, amino,        cyano, nitro, —SH, —S—(C₁-C₆)alkyl, —SO₂—(C₁-C₆)alkyl, —SO₂NH₂,        —SO₂NH—(C₁-C₆)alkyl, —SO₂NH-aryl, —SO₂-aryl, —SO—(C₁-C₆)alkyl,        —SO₂-aryl, C₁-C₆ alkoxy, C₂-C₁₀ alkenyloxy, C₂-C₁₀ alkynyloxy,        mono- or di-(C₁-C₁₀)alkylamino, —OC₁-C₁₀ alkyl-Z, or R₂₃; and

X₄ is N—OH.

Still other preferred compounds of Formula VIII are those wherein R₃ andR₄ are independently hydrogen, halo, or —N(H)R_(Z1), wherein R_(Z1) is aC₁-C₁₄ alkyl group where up to five of the carbon atoms in the alkylgroup are optionally replaced independently by R₂₂, carbonyl, ethenyl,ethynyl or a moiety selected from N, O, S, SO₂, or SO, with the provisothat two O atoms, two S atoms, or an O and S atom are not immediatelyadjacent each other,

-   -   wherein R_(Z1) is optionally substituted at any available        position with C₁-C₁₀ alkyl, C₁-C₁₀ haloalkyl, C₂-C₁₀ alkenyl,        C₂-C₁₀ alkynyl, hydroxy, carboxy, carboxamido, oxo, halo, amino,        cyano, nitro, —SH, —S—(C₁-C₆)alkyl, —SO₂—(C₁-C₆)alkyl, —SO₂NH₂,        —SO₂NH—(C₁-C₆)alkyl, —SO₂NH-aryl, —SO₂-aryl, —SO—(C₁-C₆)alkyl,        —SO₂-aryl, C₁-C₆ alkoxy, C₂-C₁₀ alkenyloxy, C₂-C₁₀ alkynyloxy,        mono- or di-(C₁-C₁₀)alkylamino, —OC₁-C₁₀ alkyl-Z, or R₂₃.

Still other preferred compounds of Formula VIII are those wherein R₃ andR₄ are independently hydrogen, halo, or —N(H)R_(Z1), wherein R_(Z1) is aC₁-C₁₄ alkyl group where up to five of the carbon atoms in the alkylgroup are optionally replaced independently by R₂₂, carbonyl, ethenyl,ethynyl or a moiety selected from N, O, S, SO₂, or SO, with the provisothat two O atoms, two S atoms, or an O and S atom are not immediatelyadjacent each other,

-   -   wherein R_(Z1) is optionally substituted at any available        position with C₁-C₁₀ alkyl, C₁-C₁₀ haloalkyl, C₂-C₁₀ alkenyl,        C₂-C₁₀ alkynyl, hydroxy, carboxy, carboxamido, oxo, halo, amino,        cyano, nitro, —SH, —S—(C₁-C₆)alkyl, —SO₂—(C₁-C₆)alkyl, —SO₂NH₂,        —SO₂NH—(C₁-C₆)alkyl, —SO₂NH-aryl, —SO₂-aryl, —SO—(C₁-C₆)alkyl,        —SO₂-aryl, C₁-C₆ alkoxy, C₂-C₁₀ alkenyloxy, C₂-C₁₀ alkynyloxy,        mono- or di-(C₁-C₁₀)alkylamino, —OC₁-C₁₀ alkyl-Z, or R₂₃; and

X₄ is O.

Still other preferred compounds of Formula VIII are those where R₃ andR₄ are independently hydrogen, halo, or —N(H)R_(Z1), wherein R_(Z1) is aC₁-C₁₄ alkyl group where up to five of the carbon atoms in the alkylgroup are optionally replaced independently by R₂₂, carbonyl, ethenyl,ethynyl or a moiety selected from N, O, S, SO₂, or SO, with the provisothat two O atoms, two S atoms, or an O and S atom are not immediatelyadjacent each other,

-   -   wherein R_(Z1) is optionally substituted at any available        position with C₁-C₁₀ alkyl, C₁-C₁₀ haloalkyl, C₂-C₁₀ alkenyl,        C₂-C₁₀ alkynyl, hydroxy, carboxy, carboxamido, oxo, halo, amino,        cyano, nitro, —SH, —S—(C₁-C₆)alkyl, —SO₂—(C₁-C₆)alkyl, —SO₂NH₂,        —SO₂NH—(C₁-C₆)alkyl, —SO₂NH-aryl, —SO₂-aryl, —SO—(C₁-C₆)alkyl,        —SO₂-aryl, C₁-C₆ alkoxy, C₂-C₁₀ alkenyloxy, C₂-C₁₀ alkynyloxy,        mono- or di-(C₁-C₁₀)alkylamino, —OC₁-C₁₀ alkyl-Z, or R₂₃; and

X₄ is N—OH.

Yet other preferred compounds of Formula VIII are those where R₃, R₄ andthe carbons to which they are attached form a 6-membered ring.

Yet other preferred compounds of Formula VIII are those where R₃, R₄ andthe carbons to which they are attached form a 6-membered ring; and X₄ isO.

Yet other preferred compounds of Formula VIII are those where R₃, R₄ andthe carbons to which they are attached form a 6-membered ring; and X₄ isN—OH.

Other preferred compounds of Formula I are those of Formula IX:

where R₁₁ is hydrogen or methyl, preferably hydrogen;R_(C) is H, C₁-C₂ alkyl, trifluoromethyl, or cyclopropyl; andR₃, R₄, and X₄ carry the same definitions as for Formula I. Preferredcompounds of Formula IX include those where R_(C) is C₁-C₂ alkyl,trifluoromethyl, or cyclopropyl.

Preferred compounds of Formula IX include those where R₃ and R₄ areindependently hydrogen, halo, or —Z₁R_(Z1), wherein Z, is —O—, —NH—,—S(O)_(p)—, or —S(O)₂NH—, wherein p is 0, 1 or 2; and R_(Z1) is a C₁-C₁₄alkyl group where up to five of the carbon atoms in the alkyl group areoptionally replaced independently by R₂₂, carbonyl, ethenyl, ethynyl ora moiety selected from N, O, S, SO₂, or SO, with the proviso that two Oatoms, two S atoms, or an O and S atom are not immediately adjacent eachother,

-   -   wherein R_(Z1) is optionally substituted at any available        position with C₁-C₁₀ alkyl, C₁-C₁₀ haloalkyl, C₂-C₁₀ alkenyl,        C₂-C₁₀ alkynyl, hydroxy, carboxy, carboxamido, oxo, halo, amino,        cyano, nitro, —SH, —S—(C₁-C₆)alkyl, —SO₂—(C₁-C₆)alkyl, —SO₂NH₂,        —SO₂NH—(C₁-C₆)alkyl, —SO₂NH-aryl, —SO₂-aryl, —SO—(C₁-C₆)alkyl,        —SO₂-aryl, C₁-C₆ alkoxy, C₂-C₁₀ alkenyloxy, C₂-C₁₀ alkynyloxy,        mono- or di-(C₁-C₁₀)alkylamino, —OC₁-C₁₀ alkyl-Z, or R₂₃.

Preferred compounds of Formula IX include those where R_(C) is methyl,ethyl, trifluoromethyl, or cyclopropyl; R₃ and R₄ are independentlyhydrogen, halo, or —Z₁R_(Z1), wherein Z, is —O—, —NH—, —S(O)_(p)—, or—S(O)₂NH—, wherein p is 0, 1 or 2; and R_(Z1) is a C₁-C₁₄ alkyl groupwhere up to five of the carbon atoms in the alkyl group are optionallyreplaced independently by R₂₂, carbonyl, ethenyl, ethynyl or a moietyselected from N, O, S, SO₂, or SO, with the proviso that two O atoms,two S atoms, or an O and S atom are not immediately adjacent each other,

-   -   wherein R_(Z1) is optionally substituted at any available        position with C₁-C₁₀ alkyl, C₁-C₁₀ haloalkyl, C₂-C₁₀ alkenyl,        C₂-C₁₀ alkynyl, hydroxy, carboxy, carboxamido, oxo, halo, amino,        cyano, nitro, —SH, —S—(C₁-C₆)alkyl, —SO₂—(C₁-C₆)alkyl, —SO₂NH₂,        —SO₂NH—(C₁-C₆)alkyl, —SO₂NH-aryl, —SO₂-aryl, —SO—(C₁-C₆)alkyl,        —SO₂-aryl, C₁-C₆ alkoxy, C₂-C₁₀ alkenyloxy, C₂-C₁₀ alkynyloxy,        mono- or di-(C₁-C₁₀)alkylamino, —OC₁-C₁₀ alkyl-Z, or R₂₃; and

X₄ is O.

Preferred compounds of Formula IX include those where R_(C) is methyl,ethyl, trifluoromethyl, or cyclopropyl; R₃ and R₄ are independentlyhydrogen, halo, or —Z₁R_(Z1), wherein Z, is —O—, —NH—, —S(O)_(p)—, or—S(O)₂NH—, wherein p is 0, 1 or 2; and R_(Z1) is a C₁-C₁₄ alkyl groupwhere up to five of the carbon atoms in the alkyl group are optionallyreplaced independently by R₂₂, carbonyl, ethenyl, ethynyl or a moietyselected from N, O, S, SO₂, or SO, with the proviso that two O atoms,two S atoms, or an O and S atom are not immediately adjacent each other,

-   -   wherein R_(Z1) is optionally substituted at any available        position with C₁-C₁₀ alkyl, C₁-C₁₀ haloalkyl, C₂-C₁₀ alkenyl,        C₂-C₁₀ alkynyl, hydroxy, carboxy, carboxamido, oxo, halo, amino,        cyano, nitro, —SH, —S—(C₁-C₆)alkyl, —SO₂—(C₁-C₆)alkyl, —SO₂NH₂,        —SO₂NH—(C₁-C₆)alkyl, —SO₂NH-aryl, —SO₂-aryl, —SO—(C₁-C₆)alkyl,        —SO₂-aryl, C₁-C₆ alkoxy, C₂-C₁₀ alkenyloxy, C₂-C₁₀ alkynyloxy,        mono- or di-(C₁-C₁₀)alkylamino, —OC₁-C₁₀ alkyl-Z, or R₂₃; and

X₄ is N—OH.

Still other preferred compounds of Formula IX include those where R₃ andR₄ are independently hydrogen, halo, or —Z₁R_(Z1), wherein Z₁ is —O— or—NH—; and R_(Z1) is a C₁-C₁₄ alkyl group where up to five of the carbonatoms in the alkyl group are optionally replaced independently by R₂₂,carbonyl, ethenyl, ethynyl or a moiety selected from N, O, S, SO₂, orSO, with the proviso that two O atoms, two S atoms, or an O and S atomare not immediately adjacent each other,

-   -   wherein R_(Z1) is optionally substituted at any available        position with C₁-C₁₀ alkyl, C₁-C₁₀ haloalkyl, C₂-C₁₀ alkenyl,        C₂-C₁₀ alkynyl, hydroxy, carboxy, carboxamido, oxo, halo, amino,        cyano, nitro, —SH, —S—(C₁-C₆)alkyl, —SO₂—(C₁-C₆)alkyl, —SO₂NH₂,        —SO₂NH—(C₁-C₆)alkyl, —SO₂NH-aryl, —SO₂-aryl, —SO—(C₁-C₆)alkyl,        —SO₂-aryl, C₁-C₆ alkoxy, C₂-C₁₀ alkenyloxy, C₂-C₁₀ alkynyloxy,        mono- or di-(C₁-C₁₀)alkylamino, —OC₁-C₁₀ alkyl-Z, or R₂₃.

Still other preferred compounds of Formula IX include those where R₃ andR₄ are independently hydrogen, halo, or —Z₁R_(Z1), wherein Z₁ is —O— or—NH—; and R_(Z1) is a C₁-C₁₄ alkyl group where up to five of the carbonatoms in the alkyl group are optionally replaced independently by R₂₂,carbonyl, ethenyl, ethynyl or a moiety selected from N, O, S, SO₂, orSO, with the proviso that two O atoms, two S atoms, or an O and S atomare not immediately adjacent each other,

-   -   wherein R_(Z1) is optionally substituted at any available        position with C₁-C₁₀ alkyl, C₁-C₁₀ haloalkyl, C₂-C₁₀ alkenyl,        C₂-C₁₀ alkynyl, hydroxy, carboxy, carboxamido, oxo, halo, amino,        cyano, nitro, —SH, —S—(C₁-C₆)alkyl, —SO₂—(C₁-C₆)alkyl, —SO₂NH₂,        —SO₂NH—(C₁-C₆)alkyl, —SO₂NH-aryl, —SO₂-aryl, —SO—(C₁-C₆)alkyl,        —SO₂-aryl, C₁-C₆ alkoxy, C₂-C₁₀ alkenyloxy, C₂-C₁₀ alkynyloxy,        mono- or di-(C₁-C₁₀)alkylamino, —OC₁-C₁₀ alkyl-Z, or R₂₃; and

X₄ is O.

Still other preferred compounds of Formula IX include those where R₃ andR₄ are independently hydrogen, halo, or —Z₁R_(Z1), wherein Z, is —O— or—NH—; and R_(Z1) is a C₁-C₁₄ alkyl group where up to five of the carbonatoms in the alkyl group are optionally replaced independently by R₂₂,carbonyl, ethenyl, ethynyl or a moiety selected from N, O, S, SO₂, orSO, with the proviso that two O atoms, two S atoms, or an O and S atomare not immediately adjacent each other,

-   -   wherein R_(Z1) is optionally substituted at any available        position with C₁-C₁₀ alkyl, C₁-C₁₀ haloalkyl, C₂-C₁₀ alkenyl,        C₂-C₁₀ alkynyl, hydroxy, carboxy, carboxamido, oxo, halo, amino,        cyano, nitro, —SH, —S—(C₁-C₆)alkyl, —SO₂—(C₁-C₆)alkyl, —SO₂NH₂,        —SO₂NH—(C₁-C₆)alkyl, —SO₂NH-aryl, —SO₂-aryl, —SO—(C₁-C₆)alkyl,        —SO₂-aryl, C₁-C₆ alkoxy, C₂-C₁₀ alkenyloxy, C₂-C₁₀ alkynyloxy,        mono- or di-(C₁-C₁₀)alkylamino, —OC₁-C₁₀ alkyl-Z, or R₂₃; and

X₄ is N—OH.

Yet other preferred compounds of Formula IX include those where R₃ andR₄ are independently hydrogen, halo, or —N(H)R_(Z1), wherein R_(Z1) is aC₁-C₁₄ alkyl group where up to five of the carbon atoms in the alkylgroup are optionally replaced independently by R₂₂, carbonyl, ethenyl,ethynyl or a moiety selected from N, O, S, SO₂, or SO, with the provisothat two O atoms, two S atoms, or an O and S atom are not immediatelyadjacent each other,

-   -   wherein R_(Z1) is optionally substituted at any available        position with C₁-C₁₀ alkyl, C₁-C₁₀ haloalkyl, C₂-C₁₀ alkenyl,        C₂-C₁₀ alkynyl, hydroxy, carboxy, carboxamido, oxo, halo, amino,        cyano, nitro, —SH, —S—(C₁-C₆)alkyl, —SO₂—(C₁-C₆)alkyl, —SO₂NH₂,        —SO₂NH—(C₁-C₆)alkyl, —SO₂NH-aryl, —SO₂-aryl, —SO—(C₁-C₆)alkyl,        —SO₂-aryl, C₁-C₆ alkoxy, C₂-C₁₀ alkenyloxy, C₂-C₁₀ alkynyloxy,        mono- or di-(C₁-C₁₀)alkylamino, —OC₁-C₁₀ alkyl-Z, or R₂₃.

Yet other preferred compounds of Formula IX include those where R₃ andR₄ are independently hydrogen, halo, or —N(H)R_(Z1), wherein R_(Z1) is aC₁-C₁₄ alkyl group where up to five of the carbon atoms in the alkylgroup are optionally replaced independently by R₂₂, carbonyl, ethenyl,ethynyl or a moiety selected from N, O, S, SO₂, or SO, with the provisothat two O atoms, two S atoms, or an O and S atom are not immediatelyadjacent each other,

-   -   wherein R_(Z1) is optionally substituted at any available        position with C₁-C₁₀ alkyl, C₁-C₁₀ haloalkyl, C₂-C₁₀ alkenyl,        C₂-C₁₀ alkynyl, hydroxy, carboxy, carboxamido, oxo, halo, amino,        cyano, nitro, —SH, —S—(C₁-C₆)alkyl, —SO₂—(C₁-C₆)alkyl, —SO₂NH₂,        —SO₂NH—(C₁-C₆)alkyl, —SO₂NH-aryl, —SO₂-aryl, —SO—(C₁-C₆)alkyl,        —SO₂-aryl, C₁-C₆ alkoxy, C₂-C₁₀ alkenyloxy, C₂-C₁₀ alkynyloxy,        mono- or di-(C₁-C₁₀)alkylamino, —OC₁-C₁₀ alkyl-Z, or R₂₃; and

X₄ is O.

Yet other preferred compounds of Formula IX include those where R₃ andR₄ are independently hydrogen, halo, or —N(H)R_(Z1), wherein R_(Z1) is aC₁-C₁₄ alkyl group where up to five of the carbon atoms in the alkylgroup are optionally replaced independently by R₂₂, carbonyl, ethenyl,ethynyl or a moiety selected from N, O, S, SO₂, or SO, with the provisothat two O atoms, two S atoms, or an O and S atom are not immediatelyadjacent each other,

-   -   wherein R_(Z1) is optionally substituted at any available        position with C₁-C₁₀ alkyl, C₁-C₁₀ haloalkyl, C₂-C₁₀ alkenyl,        C₂-C₁₀ alkynyl, hydroxy, carboxy, carboxamido, oxo, halo, amino,        cyano, nitro, —SH, —S—(C₁-C₆)alkyl, —SO₂—(C₁-C₆)alkyl, —SO₂NH₂,        —SO₂NH—(C₁-C₆)alkyl, —SO₂NH-aryl, —SO₂-aryl, —SO—(C₁-C₆)alkyl,        —SO₂-aryl, C₁-C₆ alkoxy, C₂-C₁₀ alkenyloxy, C₂-C₁₀ alkynyloxy,        mono- or di-(C₁-C₁₀)alkylamino, —OC₁-C₁₀ alkyl-Z, or R₂₃; and

X₄ is N—OH.

Still other preferred compounds of Formula IX include those where R₃, R₄and the carbons to which they are attached form a 6-membered ring.

Still other preferred compounds of Formula IX include those where R₃, R₄and the carbons to which they are attached form a 6-membered ring; andX₄ is O.

Still other preferred compounds of Formula IX include those where R₃, R₄and the carbons to which they are attached form a 6-membered ring; andX₄ is N—OH.

Preferred compounds of Formulas I-IX include compounds where X₄ is O.

Still other preferred compounds of Formulas I-IX are those where X₄ isN—OH.

Other preferred compounds of Formula I are those where R₂₁ is cyano, R₇is O, and Y is CR_(C), wherein R_(C) is H, methyl, ethyl,trifluoromethyl, or cyclopropyl.

Other preferred compounds of Formula I are those where, R₂₁ is cyano; R₇is O; and Y is CR_(C), wherein R_(C) is H, methyl, trifluoromethyl, orcyclopropyl.

Yet other preferred compounds of Formula I are those where R₂₁ is cyano,and X₃ is C substituted with two groups that are independently H orC₁-C₆ alkyl.

More preferred compounds of Formula I are those where R₂₁ is cyano, andQ₁ and Q₂ are independently C substituted with H or C₁-C₆ alkyl.

Yet other preferred compounds of Formula I are those where R₂₁ is cyano,and X₁ is C substituted with H or C₁-C₆ alkyl.

Still other preferred compounds of Formula I are those where R₂₁ iscyano, and X₂ is C substituted with two groups that are independently Hor C₁-C₄ alkyl.

In other preferred compounds of Formula I, R₂₁ is cyano, and R₃ and R₄are independently hydrogen, halo, or —Z₁R_(Z1), wherein Z₁ is —O—, —NH—,—S(O)_(p)—, or —S(O)₂NH—, wherein p is 0, 1 or 2; and R_(Z1) is a C₁-C₁₄alkyl group where up to five of the carbon atoms in the alkyl group areoptionally replaced independently by R₂₂, carbonyl, ethenyl, ethynyl ora moiety selected from N, O, S, SO₂, or SO, with the proviso that two Oatoms, two S atoms, or an O and S atom are not immediately adjacent eachother,

-   -   wherein R_(Z1) is optionally substituted at any available        position with C₁-C₁₀ alkyl, C₁-C₁₀ haloalkyl, C₂-C₁₀ alkenyl,        C₂-C₁₀ alkynyl, hydroxy, carboxy, carboxamido, oxo, halo, amino,        cyano, nitro, —SH, —S—(C₁-C₆)alkyl, —SO₂—(C₁-C₆)alkyl, —SO₂NH₂,        —SO₂NH—(C₁-C₆)alkyl, —SO₂NH-aryl, —SO₂-aryl, —SO—(C₁-C₆)alkyl,        —SO₂-aryl, C₁-C₆ alkoxy, C₂-C₁₀ alkenyloxy, C₂-C₁₀ alkynyloxy,        mono- or di-(C₁-C₁₀)alkylamino, —OC₁-C₁₀ alkyl-Z, or R₂₃.

In still other preferred compounds of Formula I, R₂₁ is cyano, and R₃and R₄ are independently hydrogen, halo, or —Z₁R_(Z1), wherein Z₁ is —O—or —NH—; and R_(Z1) is a C₁-C₁₄ alkyl group where up to five of thecarbon atoms in the alkyl group are optionally replaced independently byR₂₂, carbonyl, ethenyl, ethynyl or a moiety selected from N, O, S, SO₂,or SO, with the proviso that two O atoms, two S atoms, or an O and Satom are not immediately adjacent each other,

-   -   wherein R_(Z1) is optionally substituted at any available        position with C₁-C₁₀ alkyl, C₁-C₁₀ haloalkyl, C₂-C₁₀ alkenyl,        C₂-C₁₀ alkynyl, hydroxy, carboxy, carboxamido, oxo, halo, amino,        cyano, nitro, —SH, —S—(C₁-C₆)alkyl, —SO₂—(C₁-C₆)alkyl, —SO₂NH₂,        —SO₂NH—(C₁-C₆)alkyl, —SO₂NH-aryl, —SO₂-aryl, —SO—(C₁-C₆)alkyl,        —SO₂-aryl, C₁-C₆ alkoxy, C₂-C₁₀ alkenyloxy, C₂-C₁₀ alkynyloxy,        mono- or di-(C₁-C₁₀)alkylamino, —OC₁-C₁₀ alkyl-Z, or R₂₃.

In still other preferred compounds of Formula I, R₂₁ is cyano, and R₃and R₄ are independently hydrogen, halo, or —N(H)R_(Z1), wherein R_(Z1)is a C₁-C₁₄ alkyl group where up to five of the carbon atoms in thealkyl group are optionally replaced independently by R₂₂, carbonyl,ethenyl, ethynyl or a moiety selected from N, O, S, SO₂, or SO, with theproviso that two O atoms, two S atoms, or an O and S atom are notimmediately adjacent each other,

-   -   wherein R_(Z1) is optionally substituted at any available        position with C₁-C₁₀ alkyl, C₁-C₁₀ haloalkyl, C₂-C₁₀ alkenyl,        C₂-C₁₀ alkynyl, hydroxy, carboxy, carboxamido, oxo, halo, amino,        cyano, nitro, —SH, —S—(C₁-C₆)alkyl, —SO₂—(C₁-C₆)alkyl, —SO₂NH₂,        —SO₂NH—(C₁-C₆)alkyl, —SO₂NH-aryl, —SO₂-aryl, —SO—(C₁-C₆)alkyl,        —SO₂-aryl, C₁-C₆ alkoxy, C₂-C₁₀ alkenyloxy, C₂-C₁₀ alkynyloxy,        mono- or di-(C₁-C₁₀)alkylamino, —OC₁-C₁₀ alkyl-Z, or R₂₃.

Other more preferred compounds of Formula I are those where R₂₁ iscyano, and R₄ is H, C₁-C₄ alkyl or halogen.

Particularly preferred compounds of Formula I include those where

-   R₂₁ is cyano, and-   X₂ is C substituted with two groups that are independently H or    C₁-C₄ alkyl;-   X₁ is C substituted with H or C₁-C₆ alkyl;-   Q₁ and Q₂ are independently C substituted with H or C₁-C₆ alkyl;-   X₃ is C substituted with two groups that are independently H or    C₁-C₆ alkyl;-   R₇ is O;-   Y is CR_(C) wherein R_(C) is H or CH₃; and-   R₃ and R₄ are independently hydrogen, halo, or —Z₁R_(Z1), wherein Z₁    is —O—, —NH—, —S(O)_(p)—, or —S(O)₂NH—, wherein p is 0, 1 or 2;-   and R_(Z1) is a C₁-C₁₄ alkyl group where up to five of the carbon    atoms in the alkyl group are optionally replaced independently by    R₂₂, carbonyl, ethenyl, ethynyl or a moiety selected from N, O, S,    SO₂, or SO, with the proviso that two O atoms, two S atoms, or an O    and S atom are not immediately adjacent each other,    -   wherein R_(Z1) is optionally substituted at any available        position with C₁-C₁₀ alkyl, C₁-C₁₀ haloalkyl, C₂-C₁₀ alkenyl,        C₂-C₁₀ alkynyl, hydroxy, carboxy, carboxamido, oxo, halo, amino,        cyano, nitro, —SH, —S—(C₁-C₆)alkyl, —SO₂—(C₁-C₆)alkyl, —SO₂NH₂,        —SO₂NH—(C₁-C₆)alkyl, —SO₂NH-aryl, —SO₂-aryl, —SO—(C₁-C₆)alkyl,        —SO₂-aryl, C₁-C₆ alkoxy, C₂-C₁₀ alkenyloxy, C₂-C₁₀ alkynyloxy,        mono- or di-(C₁-C₁₀)alkylamino, —OC₁-C₁₀ alkyl-Z, or R₂₃; and-   n is 1 or 2.    Such compounds are referred to herein as compounds of Formula X.

Preferred compounds of Formula X include those where

-   R₁ and R₂ are independently H or C₁-C₄ alkyl;-   Q₁ and Q₂ are both CH;-   X₂ is C substituted with two independently selected C₁-C₄ alkyl    groups; and-   n is 1.

Particularly preferred compounds of Formula I include those where R₂₁ iscyano. Such compounds are referred to hereinafter as compounds ofFormula XI.

Preferred compounds of Formula XI are those where R₃ and R₄ areindependently halogen or hydrogen.

Preferred compounds of Formula XI are those where R₃ is halogen.

Preferred compounds of Formula XI are those where R₃ is hydrogen and R₄is halogen.

Preferred compounds of Formula XI are those where R₄ is halogen.

Other preferred compounds of Formula I include those of Formula XII:

R₃ and R₄ are independently halogen or hydrogen, provided that at leastone of R₃ and R₄ is halogen, and X₁, R_(C), R₅ and R₆ are as defined forFormula I.

Preferred compounds of Formula XII include those where X₁ is N.

Preferred compounds of Formula XII include those where X₁ is CR_(C),wherein R_(C) is hydrogen, methyl, ethyl, cyclopropyl,cyclopropylmethyl, fluoromethyl, difluoromethyl, or trifluoromethyl.

Preferred compounds of Formula XII are those where R₃ is halogen.

Other preferred compounds of Formula XII are those where R₄ is halogen.

Still other preferred compounds of Formula XII are those where R₃ isfluoro and R₄ is hydrogen or fluoro.

Particularly preferred compounds of Formula XII are those where R₄ isfluoro and R₃ is hydrogen, bromo, or fluoro.

Other particularly preferred compounds of Formula XII are those where R₄is hydrogen.

Still other preferred compounds of Formula XII are those where R₃ ishydrogen.

Particularly preferred compounds of Formula XII include those where R₃and R₄ are fluoro.

Preferred compounds of Formula XII are those where R₃ and R₄ are bromoand fluoro respectively.

Yet other preferred compounds of Formula I include those of FormulaXIII,

wherein R₁-R₆, X₄, X₁, and R_(C) are as defined in Formula I.

Preferred compounds of Formula XIII include those where R₃ and R₄ areindependently hydrogen, halo, or —Z₁R_(Z1), wherein Z₁ is —O—, —NH—,—S(O)_(p)—, or —S(O)₂NH—, wherein p is 0, 1 or 2; and R_(Z1) is a C₁-C₁₄alkyl group where up to five of the carbon atoms in the alkyl group areoptionally replaced independently by R₂₂, carbonyl, ethenyl, ethynyl ora moiety selected from N, O, S, SO₂, or SO, with the proviso that two Oatoms, two S atoms, or an O and S atom are not immediately adjacent eachother,

-   -   wherein R_(Z1) is optionally substituted at any available        position with C₁-C₁₀ alkyl, C₁-C₁₀ haloalkyl, C₂-C₁₀ alkenyl,        C₂-C₁₀ alkynyl, hydroxy, carboxy, carboxamido, oxo, halo, amino,        cyano, nitro, —SH, —S—(C₁-C₆)alkyl, —SO₂—(C₁-C₆)alkyl, —SO₂NH₂,        —SO₂NH—(C₁-C₆)alkyl, —SO₂NH-aryl, —SO₂-aryl, —SO—(C₁-C₆)alkyl,        —SO₂-aryl, C₁-C₆ alkoxy, C₂-C₁₀ alkenyloxy, C₂-C₁₀ alkynyloxy,        mono- or di-(C₁-C₁₀)alkylamino, —OC₁-C₁₀ alkyl-Z, or R₂₃.

Other preferred compounds of Formula XIII are those where R₃ and R₄ areindependently hydrogen, halo, or —Z₁R_(Z1), wherein Z, is —O— or —NH—;and R_(Z1) is a C₁-C₁₄ alkyl group where up to five of the carbon atomsin the alkyl group are optionally replaced independently by R₂₂,carbonyl, ethenyl, ethynyl or a moiety selected from N, O, S, SO₂, orSO, with the proviso that two O atoms, two S atoms, or an O and S atomare not immediately adjacent each other,

-   -   wherein R_(Z1) is optionally substituted at any available        position with C₁-C₁₀ alkyl, C₁-C₁₀ haloalkyl, C₂-C₁₀ alkenyl,        C₂-C₁₀ alkynyl, hydroxy, carboxy, carboxamido, oxo, halo, amino,        cyano, nitro, —SH, —S—(C₁-C₆)alkyl, —SO₂—(C₁-C₆)alkyl, —SO₂NH₂,        —SO₂NH—(C₁-C₆)alkyl, —SO₂NH-aryl, —SO₂-aryl, —SO—(C₁-C₆)alkyl,        —SO₂-aryl, C₁-C₆ alkoxy, C₂-C₁₀ alkenyloxy, C₂-C₁₀ alkynyloxy,        mono- or di-(C₁-C₁₀)alkylamino, —OC₁-C₁₀ alkyl-Z, or R₂₃.

Other preferred compounds of Formula XIII are those where R₃ and R₄ areindependently hydrogen, halo, or —N(H)R_(Z1), wherein R_(Z1) is a C₁-C₁₄alkyl group where up to five of the carbon atoms in the alkyl group areoptionally replaced independently by R₂₂, carbonyl, ethenyl, ethynyl ora moiety selected from N, O, S, SO₂, or SO, with the proviso that two Oatoms, two S atoms, or an O and S atom are not immediately adjacent eachother,

-   -   wherein R_(Z1) is optionally substituted at any available        position with C₁-C₁₀ alkyl, C₁-C₁₀ haloalkyl, C₂-C₁₀ alkenyl,        C₂-C₁₀ alkynyl, hydroxy, carboxy, carboxamido, oxo, halo, amino,        cyano, nitro, —SH, —S—(C₁-C₆)alkyl, —SO₂—(C₁-C₆)alkyl, —SO₂NH₂,        —SO₂NH—(C₁-C₆)alkyl, —SO₂NH-aryl, —SO₂-aryl, —SO—(C₁-C₆)alkyl,        —SO₂-aryl, C₁-C₆ alkoxy, C₂-C₁₀ alkenyloxy, C₂-C₁₀ alkynyloxy,        mono- or di-(C₁-C₁₀)alkylamino, —OC₁-C₁₀ alkyl-Z, or R₂₃.

In still other preferred compounds of Formula XIII R₃, R₄ and thecarbons to which they are attached form a 6-membered ring.

In more preferred aspects, the previously described preferredembodiments of Formula XIII include compounds wherein X₁ is N or CR_(C),wherein R_(C) is hydrogen, methyl, ethyl, cyclopropyl,cyclopropylmethyl, fluoromethyl, difluoromethyl, or trifluoromethyl.

In more preferred aspects, the previously described preferredembodiments of Formula XIII include compounds wherein X₁ is N.

In more preferred aspects, the previously described preferredembodiments of Formula XIII include compounds wherein X₁ is CR_(C),wherein R_(C) is hydrogen, methyl, ethyl, cyclopropyl,cyclopropylmethyl, fluoromethyl, difluoromethyl, or trifluoromethyl.

Other preferred compounds of Formula I include those of Formula XIV,

wherein R_(C) is —H, —CH₃, —CF₃, or cyclopropyl; and

-   R₃ and R₄ are independently halogen or hydrogen, provided that at    least one of R₃ and R₄ is halogen, and R₅ and R₆ are as defined for    Formula I.

Yet other preferred compounds of Formula II through XIV are those whereR₂₁ is cyano; R₇ is O; and Y is CH or C(CH₃).

Yet other preferred compounds of Formula II through XIV are those whereR₂₁ is cyano; and R₃ and R₄ are independently hydrogen, halo, or—Z₁R_(Z1), wherein Z₁ is —O—, —NH—, —S(O)_(p)—, or —S(O)₂NH—, wherein pis 0, 1 or 2; and R_(Z1) is a C₁-C₁₄ alkyl group where up to five of thecarbon atoms in the alkyl group are optionally replaced independently byR₂₂, carbonyl, ethenyl, ethynyl or a moiety selected from N, O, S, SO₂,or SO, with the proviso that two O atoms, two S atoms, or an O and Satom are not immediately adjacent each other,

-   -   wherein R_(Z1) is optionally substituted at any available        position with C₁-C₁₀ alkyl, C₁-C₁₀ haloalkyl, C₂-C₁₀ alkenyl,        C₂-C₁₀ alkynyl, hydroxy, carboxy, carboxamido, oxo, halo, amino,        cyano, nitro, —SH, —S—(C₁-C₆)alkyl, —SO₂—(C₁-C₆)alkyl, —SO₂NH₂,        —SO₂NH—(C₁-C₆)alkyl, —SO₂NH-aryl, —SO₂-aryl, —SO—(C₁-C₆)alkyl,        —SO₂-aryl, C₁-C₆ alkoxy, C₂-C₁₀ alkenyloxy, C₂-C₁₀ alkynyloxy,        mono- or di-(C₁-C₁₀)alkylamino, —OC₁-C₁₀ alkyl-Z, or R₂₃.

Yet other preferred compounds of Formula II through XIV are those whereR₂₁ is cyano; and R₃ and R₄ are independently hydrogen, halo, or—Z₁R_(Z1), wherein Z₁ is —O— or —NH—; and R_(Z1) is a C₁-C₁₄ alkyl groupwhere up to five of the carbon atoms in the alkyl group are optionallyreplaced independently by R₂₂, carbonyl, ethenyl, ethynyl or a moietyselected from N, O, S, SO₂, or SO, with the proviso that two O atoms,two S atoms, or an O and S atom are not immediately adjacent each other,

-   -   wherein R_(Z1) is optionally substituted at any available        position with C₁-C₁₀ alkyl, C₁-C₁₀ haloalkyl, C₂-C₁₀ alkenyl,        C₂-C₁₀ alkynyl, hydroxy, carboxy, carboxamido, oxo, halo, amino,        cyano, nitro, —SH, —S—(C₁-C₆)alkyl, —SO₂—(C₁-C₆)alkyl, —SO₂NH₂,        —SO₂NH—(C₁-C₆)alkyl, —SO₂NH-aryl, —SO₂-aryl, —SO—(C₁-C₆)alkyl,        —SO₂-aryl, C₁-C₆ alkoxy, C₂-C₁₀ alkenyloxy, C₂-C₁₀ alkynyloxy,        mono- or di-(C₁-C₁₀)alkylamino, —OC₁-C₁₀ alkyl-Z, or R₂₃.

Yet other preferred compounds of Formula II through XIV are those whereR₂₁ is cyano; and R₃ and R₄ are independently hydrogen, halo, or—N(H)R_(Z1), wherein R_(Z1) is a C₁-C₁₄ alkyl group where up to five ofthe carbon atoms in the alkyl group are optionally replacedindependently by R₂₂, carbonyl, ethenyl, ethynyl or a moiety selectedfrom N, O, S, SO₂, or SO, with the proviso that two O atoms, two Satoms, or an O and S atom are not immediately adjacent each other,

-   -   wherein R_(Z1) is optionally substituted at any available        position with C₁-C₁₀ alkyl, C₁-C₁₀ haloalkyl, C₂-C₁₀ alkenyl,        C₂-C₁₀ alkynyl, hydroxy, carboxy, carboxamido, oxo, halo, amino,        cyano, nitro, —SH, —S—(C₁-C₆)alkyl, —SO₂—(C₁-C₆)alkyl, —SO₂NH₂,        —SO₂NH—(C₁-C₆)alkyl, —SO₂NH-aryl, —SO₂-aryl, —SO—(C₁-C₆)alkyl,        —SO₂-aryl, C₁-C₆ alkoxy, C₂-C₁₀ alkenyloxy, C₂-C₁₀ alkynyloxy,        mono- or di-(C₁-C₁₀)alkylamino, —OC₁-C₁₀ alkyl-Z, or R₂₃.

In another aspect, the invention encompasses compounds of Formula I,wherein Y is CR_(C), wherein R_(C) is —H, C₁-C₁₀ alkyl, C₁-C₁₀haloalkyl, or C₃-C₇ cycloalkyl.

In another aspect, the invention encompasses compounds of Formula I,wherein Y is CH.

In another aspect, the invention encompasses compounds of Formula I,wherein Y is CR_(C), wherein R_(C) is C₁-C₁₀ alkyl, C₁-C₁₀ haloalkyl, orC₃-C₇ cycloalkyl.

In another aspect, the invention encompasses compounds of Formula I,wherein Y is CR_(C), wherein R_(C) is methyl, ethyl, trifluoromethyl, orcyclopropyl.

In another aspect, the invention encompasses compounds of Formula I,wherein Y is CR_(C), wherein R_(C) is methyl.

In another aspect, the invention encompasses compounds of Formula I,wherein Y is CR_(C), wherein R_(C) is cyclopropyl.

Yet other preferred compounds of Formula I include those of Formula XV,

wherein X₁-X₄, Q₁, Q₂, R_(C), and R₁-R₄ are as defined in Formula I.

Preferred compounds of formula XV are those where Q₁ and Q₂ are eachindependently hydrogen or C₁-C₆ alkyl.

Other preferred compounds of formula XV are those where R_(C) isC₁-C₆alkyl, C₃-C₇cycloalkyl, C₁-C₆ haloalkyl,C₃-C₇cycloalkyl(C₁-C₆)alkyl, or heterocycloalkyl.

More preferred compounds of Formula XV include those where R_(C) isC₃-C₇cycloalkyl, C₁-C₆ haloalkyl, heterocycloalkyl, orC₃-C₇cycloalkyl(C₁-C₆)alkyl.

Particularly preferred compounds of Formula XV include those where R_(C)is C₁-C₃alkyl, C₃-C₅cycloalkyl, C₃-C₅cycloalkyl(C₁-C₃)alkyl, or C₁-C₂haloalkyl.

Additional preferred compounds of Formula XV include those where R₃ andR₄ are independently hydrogen, halo, or —Z₁R_(Z1), wherein Z, is —O—,—NH—, —S(O)_(p)—, or —S(O)₂NH—, wherein p is 0, 1 or 2; and R_(Z1) is aC₁-C₁₄ alkyl group where up to five of the carbon atoms in the alkylgroup are optionally replaced independently by R₂₂, carbonyl, ethenyl,ethynyl or a moiety selected from N, O, S, SO₂, or SO, with the provisothat two O atoms, two S atoms, or an O and S atom are not immediatelyadjacent each other,

-   -   wherein R_(Z1) is optionally substituted at any available        position with C₁-C₁₀ alkyl, C₁-C₁₀ haloalkyl, C₂-C₁₀ alkenyl,        C₂-C₁₀ alkynyl, hydroxy, carboxy, carboxamido, oxo, halo, amino,        cyano, nitro, —SH, —S—(C₁-C₆)alkyl, —SO₂—(C₁-C₆)alkyl, —SO₂NH₂,        —SO₂NH—(C₁-C₆)alkyl, —SO₂NH-aryl, —SO₂-aryl, —SO—(C₁-C₆)alkyl,        —SO₂-aryl, C₁-C₆ alkoxy, C₂-C₁₀ alkenyloxy, C₂-C₁₀ alkynyloxy,        mono- or di-(C₁-C₁₀)alkylamino, —OC₁-C₁₀ alkyl-Z, or R₂₃.

Other preferred compounds of Formula XV include those where R₃ and R₄are independently hydrogen, halo, or —Z₁R_(Z1), wherein Z₁ is —O— or—NH—; and R_(Z1) is a C₁-C₁₄ alkyl group where up to five of the carbonatoms in the alkyl group are optionally replaced independently by R₂₂,carbonyl, ethenyl, ethynyl or a moiety selected from N, O, S, SO₂, orSO, with the proviso that two O atoms, two S atoms, or an O and S atomare not immediately adjacent each other,

-   -   wherein R_(Z1) is optionally substituted at any available        position with C₁-C₁₀ alkyl, C₁-C₁₀ haloalkyl, C₂-C₁₀ alkenyl,        C₂-C₁₀ alkynyl, hydroxy, carboxy, carboxamido, oxo, halo, amino,        cyano, nitro, —SH, —S—(C₁-C₆)alkyl, —SO₂—(C₁-C₆)alkyl, —SO₂NH₂,        —SO₂NH—(C₁-C₆)alkyl, —SO₂NH-aryl, —SO₂-aryl, —SO—(C₁-C₆)alkyl,        —SO₂-aryl, C₁-C₆ alkoxy, C₂-C₁₀ alkenyloxy, C₂-C₁₀ alkynyloxy,        mono- or di-(C₁-C₁₀)alkylamino, —OC₁-C₁₀ alkyl-Z, or R₂₃.

Still other preferred compounds of Formula XV are those wherein R₃ andR₄ are independently hydrogen, halo, or —N(H)R_(Z1), wherein R_(Z1) is aC₁-C₁₄ alkyl group where up to five of the carbon atoms in the alkylgroup are optionally replaced independently by R₂₂, carbonyl, ethenyl,ethynyl or a moiety selected from N, O, S, SO₂, or SO, with the provisothat two O atoms, two S atoms, or an O and S atom are not immediatelyadjacent each other,

-   -   wherein R_(Z1) is optionally substituted at any available        position with C₁-C₁₀ alkyl, C₁-C₁₀ haloalkyl, C₂-C₁₀ alkenyl,        C₂-C₁₀ alkynyl, hydroxy, carboxy, carboxamido, oxo, halo, amino,        cyano, nitro, —SH, —S—(C₁-C₆)alkyl, —SO₂—(C₁-C₆)alkyl, —SO₂NH₂,        —SO₂NH—(C₁-C₆)alkyl, —SO₂NH-aryl, —SO₂-aryl, —SO—(C₁-C₆)alkyl,        —SO₂-aryl, C₁-C₆ alkoxy, C₂-C₁₀ alkenyloxy, C₂-C₁₀ alkynyloxy,        mono- or di-(C₁-C₁₀)alkylamino, —OC₁-C₁₀ alkyl-Z, or R₂₃.

More preferred compounds of Formula XV are those wherein R₃ and R₄ areindependently hydrogen, —N(H)—R₂₂—R_(Z2), wherein

-   -   R_(Z2) is a C₁-C₁₃ alkyl group where up to five of the carbon        atoms in the alkyl group are optionally replaced independently        by R₂₂, carbonyl, ethenyl, ethynyl or a moiety selected from N,        O, S, SO₂, or SO, with the proviso that two O atoms, two S        atoms, or an O and S atom are not immediately adjacent each        other,        -   wherein R_(Z2) is optionally substituted at any available            position with C₁-C₁₀ alkyl, C₁-C₁₀ haloalkyl, C₂-C₁₀            alkenyl, C₂-C₁₀ alkynyl, hydroxy, carboxy, carboxamido, oxo,            halo, amino, cyano, nitro, —SH, —S—(C₁-C₆)alkyl,            —SO₂—(C₁-C₆) alkyl, —SO₂NH₂, —SO₂NH—(C₁-C₆)alkyl,            —SO₂NH-aryl, —SO₂-aryl, —SO—(C₁-C₆)alkyl, —SO₂-aryl, C₁-C₆            alkoxy, C₂-C₁₀ alkenyloxy, C₂-C₁₀ alkynyloxy, mono- or            di-(C₁-C₁₀)alkylamino, —OC₁-C₁₀ alkyl-Z, or R₂₃.            Such compounds are referred to herein as compounds of            Formula XVa.

Preferred compounds of Formula XVa are those where X₁ is N.

Preferred compounds of Formula XVa are those where R₂₂ is heteroaryl,aryl, saturated C₃-C₁₀ cycloalkyl, or saturated C₂-C₁₀ heterocycloalkyl.

More preferred compounds of Formula XVa are those where R₂₂ isheteroaryl, aryl, saturated C₃-C₁₀ cycloalkyl, or saturated C₂-C₁₀heterocycloalkyl; and X₁ is N.

Particularly preferred compounds of Formula XVa are those where R₂₂ issaturated C₃-C₇ cycloalkyl, or saturated C₂-C₆ heterocycloalkyl.

Particularly preferred compounds of Formula XVa are those where R₂₂ issaturated C₃-C₇ cycloalkyl, or saturated C₂-C₆ heterocycloalkyl and X₁is N.

Preferred compounds of Formula XV are those where X₁ is N. Suchcompounds are referred to herein as compounds of Formula XVI.

Preferred compounds of Formula XVI include those where R₃ and R₄ areindependently hydrogen, halo, or —Z₁R_(Z1), wherein Z₁ is —O—, —NH—,—S(O)_(p)—, or —S(O)₂NH—, wherein p is 0, 1 or 2; and R_(Z1) is a C₁-C₁₄alkyl group where up to five of the carbon atoms in the alkyl group areoptionally replaced independently by R₂₂, carbonyl, ethenyl, ethynyl ora moiety selected from N, O, S, SO₂, or SO, with the proviso that two Oatoms, two S atoms, or an O and S atom are not immediately adjacent eachother,

-   -   wherein R_(Z1) is optionally substituted at any available        position with C₁-C₁₀ alkyl, C₁-C₁₀ haloalkyl, C₂-C₁₀ alkenyl,        C₂-C₁₀ alkynyl, hydroxy, carboxy, carboxamido, oxo, halo, amino,        cyano, nitro, —SH, —S—(C₁-C₆)alkyl, —SO₂—(C₁-C₆)alkyl, —SO₂NH₂,        —SO₂NH—(C₁-C₆)alkyl, —SO₂NH-aryl, —SO₂-aryl, —SO—(C₁-C₆)alkyl,        —SO₂-aryl, C₁-C₆ alkoxy, C₂-C₁₀ alkenyloxy, C₂-C₁₀ alkynyloxy,        mono- or di-(C₁-C₁₀)alkylamino, —OC₁-C₁₀ alkyl-Z, or R₂₃.

Preferred compounds of Formula XVI include those where R₃ and R₄ areindependently hydrogen, halo, or —Z₁R_(Z1), wherein Z₁ is —O—, —NH—,—S(O)_(p)—, or —S(O)₂NH—, wherein p is 0, 1 or 2; and R_(Z1) is a C₁-C₁₄alkyl group where up to five of the carbon atoms in the alkyl group areoptionally replaced independently by R₂₂, carbonyl, ethenyl, ethynyl ora moiety selected from N, O, S, SO₂, or SO, with the proviso that two Oatoms, two S atoms, or an O and S atom are not immediately adjacent eachother,

-   -   wherein R_(Z1) is optionally substituted at any available        position with C₁-C₁₀ alkyl, C₁-C₁₀ haloalkyl, C₂-C₁₀ alkenyl,        C₂-C₁₀ alkynyl, hydroxy, carboxy, carboxamido, oxo, halo, amino,        cyano, nitro, —SH, —S—(C₁-C₆)alkyl, —SO₂—(C₁-C₆)alkyl, —SO₂NH₂,        —SO₂NH—(C₁-C₆)alkyl, —SO₂NH-aryl, —SO₂-aryl, —SO—(C₁-C₆)alkyl,        —SO₂-aryl, C₁-C₆ alkoxy, C₂-C₁₀ alkenyloxy, C₂-C₁₀ alkynyloxy,        mono- or di-(C₁-C₁₀)alkylamino, —OC₁-C₁₀ alkyl-Z, or R₂₃; and X₄        is O.

Preferred compounds of Formula XVI include those where R₃ and R₄ areindependently hydrogen, halo, or —Z₁R_(Z1), wherein Z₁ is —O—, —NH—,—S(O)_(p)—, or —S(O)₂NH—, wherein p is 0, 1 or 2; and R_(Z1) is a C₁-C₁₄alkyl group where up to five of the carbon atoms in the alkyl group areoptionally replaced independently by R₂₂, carbonyl, ethenyl, ethynyl ora moiety selected from N, O, S, SO₂, or SO, with the proviso that two Oatoms, two S atoms, or an O and S atom are not immediately adjacent eachother,

-   -   wherein R_(Z1) is optionally substituted at any available        position with C₁-C₁₀ alkyl, C₁-C₁₀ haloalkyl, C₂-C₁₀ alkenyl,        C₂-C₁₀ alkynyl, hydroxy, carboxy, carboxamido, oxo, halo, amino,        cyano, nitro, —SH, —S—(C₁-C₆)alkyl, —SO₂—(C₁-C₆)alkyl, —SO₂NH₂,        —SO₂NH—(C₁-C₆)alkyl, —SO₂NH-aryl, —SO₂-aryl, —SO—(C₁-C₆)alkyl,        —SO₂-aryl, C₁-C₆ alkoxy, C₂-C₁₀ alkenyloxy, C₂-C₁₀ alkynyloxy,        mono- or di-(C₁-C₁₀)alkylamino, —OC₁-C₁₀ alkyl-Z, or R₂₃; and X₄        is N—OH.

Other preferred compounds of Formula XVI include those where R₃ and R₄are independently hydrogen, halo, or —Z₁R_(Z1), wherein Z₁ is —O— or—NH—; and R_(Z1) is a C₁-C₁₄ alkyl group where up to five of the carbonatoms in the alkyl group are optionally replaced independently by R₂₂,carbonyl, ethenyl, ethynyl or a moiety selected from N, O, S, SO₂, orSO, with the proviso that two O atoms, two S atoms, or an O and S atomare not immediately adjacent each other,

-   -   wherein R_(Z1) is optionally substituted at any available        position with C₁-C₁₀ alkyl, C₁-C₁₀ haloalkyl, C₂-C₁₀-alkenyl,        C₂-C₁₀ alkynyl, hydroxy, carboxy, carboxamido, oxo, halo, amino,        cyano, nitro, —SH, —S—(C₁-C₆)alkyl, —SO₂—(C₁-C₆)alkyl, —SO₂NH₂,        —SO₂NH—(C₁-C₆)alkyl, —SO₂NH-aryl, —SO₂-aryl, —SO—(C₁-C₆)alkyl,        —SO₂-aryl, C₁-C₆ alkoxy, C₂-C₁₀ alkenyloxy, C₂-C₁₀ alkynyloxy,        mono- or di-(C₁-C₁₀)alkylamino, —OC₁-C₁₀ alkyl-Z, or R₂₃.

Other preferred compounds of Formula XVI include those where R₃ and R₄are independently hydrogen, halo, or —Z₁R_(Z1), wherein Z₁ is —O— or—NH—; and R_(Z1) is a C₁-C₁₄ alkyl group where up to five of the carbonatoms in the alkyl group are optionally replaced independently by R₂₂,carbonyl, ethenyl, ethynyl or a moiety selected from N, O, S, SO₂, orSO, with the proviso that two O atoms, two S atoms, or an O and S atomare not immediately adjacent each other,

-   -   wherein R_(Z1) is optionally substituted at any available        position with C₁-C₁₀ alkyl, C₁-C₁₀ haloalkyl, C₂-C₁₀ alkenyl,        C₂-C₁₀ alkynyl, hydroxy, carboxy, carboxamido, oxo, halo, amino,        cyano, nitro, —SH, —S—(C₁-C₆)alkyl, —SO₂—(C₁-C₆)alkyl, —SO₂NH₂,        —SO₂NH—(C₁-C₆)alkyl, —SO₂NH-aryl, —SO₂-aryl, —SO—(C₁-C₆)alkyl,        —SO₂-aryl, C₁-C₆ alkoxy, C₂-C₁₀ alkenyloxy, C₂-C₁₀ alkynyloxy,        mono- or di-(C₁-C₁₀)alkylamino, —OC₁-C₁₀ alkyl-Z, or R₂₃; and X₄        is O.

Other preferred compounds of Formula XVI include those where R₃ and R₄are independently hydrogen, halo, or —Z₁R_(Z1), wherein Z₁ is —O— or—NH—; and R_(Z1) is a C₁-C₁₄ alkyl group where up to five of the carbonatoms in the alkyl group are optionally replaced independently by R₂₂,carbonyl, ethenyl, ethynyl or a moiety selected from N, O, S, SO₂, orSO, with the proviso that two O atoms, two S atoms, or an O and S atomare not immediately adjacent each other,

-   -   wherein R_(Z1) is optionally substituted at any available        position with C₁-C₁₀ alkyl, C₁-C₁₀ haloalkyl, C₂-C₁₀ alkenyl,        C₂-C₁₀ alkynyl, hydroxy, carboxy, carboxamido, oxo, halo, amino,        cyano, nitro, —SH, —S—(C₁-C₆)alkyl, —SO₂—(C₁-C₆)alkyl, —SO₂NH₂,        —SO₂NH—(C₁-C₆)alkyl, —SO₂NH-aryl, —SO₂-aryl, —SO—(C₁-C₆)alkyl,        —SO₂-aryl, C₁-C₆ alkoxy, C₂-C₁₀ alkenyloxy, C₂-C₁₀ alkynyloxy,        mono- or di-(C₁-C₁₀)alkylamino, —OC₁-C₁₀ alkyl-Z, or R₂₃; and X₄        is N—OH.

Still other preferred compounds of Formula XVI are those wherein R₃ andR₄ are independently hydrogen, halo, or —N(H)R_(Z1), wherein R_(Z1) is aC₁-C₁₄ alkyl group where up to five of the carbon atoms in the alkylgroup are optionally replaced independently by R₂₂, carbonyl, ethenyl,ethynyl or a moiety selected from N, O, S, SO₂, or SO, with the provisothat two O atoms, two S atoms, or an O and S atom are not immediatelyadjacent each other,

-   wherein R_(Z1) is optionally substituted at any available position    with C₁-C₁₀ alkyl, C₁-C₁₀ haloalkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl,    hydroxy, carboxy, carboxamido, oxo, halo, amino, cyano, nitro, —SH,    —S—(C₁-C₆)alkyl, —SO₂—(C₁-C₆)alkyl, —SO₂NH₂, —SO₂NH—(C₁-C₆)alkyl,    —SO₂NH-aryl, —SO₂-aryl, —SO—(C₁-C₆)alkyl, —SO₂-aryl, C₁-C₆ alkoxy,    C₂-C₁₀ alkenyloxy, C₂-C₁₀ alkynyloxy, mono- or    di-(C₁-C₁₀)alkylamino, —OC₁-C₁₀ alkyl-Z, or R₂₃.

Still other preferred compounds of Formula XVI are those wherein R₃ andR₄ are independently hydrogen, halo, or —N(H)R_(Z1), wherein R_(Z1) is aC₁-C₁₄ alkyl group where up to five of the carbon atoms in the alkylgroup are optionally replaced independently by R₂₂, carbonyl, ethenyl,ethynyl or a moiety selected from N, O, S, SO₂, or SO, with the provisothat two O atoms, two S atoms, or an O and S atom are not immediatelyadjacent each other,

-   -   wherein R_(Z1) is optionally substituted at any available        position with C₁-C₁₀ alkyl, C₁-C₁₀ haloalkyl, C₂-C₁₀ alkenyl,        C₂-C₁₀ alkynyl, hydroxy, carboxy, carboxamido, oxo, halo, amino,        cyano, nitro, —SH, —S—(C₁-C₆)alkyl, —SO₂—(C₁-C₆)alkyl, —SO₂NH₂,        —SO₂NH—(C₁-C₆)alkyl, —SO₂NH-aryl, —SO₂-aryl, —SO—(C₁-C₆)alkyl,        —SO₂-aryl, C₁-C₆ alkoxy, C₂-C₁₀ alkenyloxy, C₂-C₁₀ alkynyloxy,        mono- or di-(C₁-C₁₀)alkylamino, —OC₁-C₁₀ alkyl-Z, or R₂₃; and

X₄ is O.

Still other preferred compounds of Formula XVI are those where R₃ and R₄are independently hydrogen, halo, or —N(H)R_(Z1), wherein R_(Z1) is aC₁-C₁₄ alkyl group where up to five of the carbon atoms in the alkylgroup are optionally replaced independently by R₂₂, carbonyl, ethenyl,ethynyl or a moiety selected from N, O, S, SO₂, or SO, with the provisothat two O atoms, two S atoms, or an O and S atom are not immediatelyadjacent each other,

-   -   wherein R_(Z1) is optionally substituted at any available        position with C₁-C₁₀ alkyl, C₁-C₁₀ haloalkyl, C₂-C₁₀ alkenyl,        C₂-C₁₀ alkynyl, hydroxy, carboxy, carboxamido, oxo, halo, amino,        cyano, nitro, —SH, —S—(C₁-C₆)alkyl, —SO₂—(C₁-C₆)alkyl, —SO₂NH₂,        —SO₂NH—(C₁-C₆)alkyl, —SO₂NH-aryl, —SO₂-aryl, —SO—(C₁-C₆)alkyl,        —SO₂-aryl, C₁-C₆ alkoxy, C₂-C₁₀ alkenyloxy, C₂-C₁₀ alkynyloxy,        mono- or di-(C₁-C₁₀)alkylamino, —OC₁-C₁₀ alkyl-Z, or R₂₃; and

X₄ is N—OH.

Yet other preferred compounds of Formula XVI are those where R₃, R₄ andthe carbons to which they are attached form a 6-membered ring.

Yet other preferred compounds of Formula XVI are those where R₃, R₄ andthe carbons to which they are attached form a 6-membered ring; and X₄ isO.

Yet other preferred compounds of Formula XVI are those where R₃, R₄ andthe carbons to which they are attached form a 6-membered ring; and X₄ isN—OH.

Yet other preferred compounds of Formula XVI are those where R₃ and R₄are both —H.

Yet other preferred compounds of Formula XVI are those where R₃ and R₄are both —H; and X₄ is O.

Yet other preferred compounds of Formula XVIII are those where R₃ and R₄are both —H; and X₄ is N—OH.

In another aspect, the invention provides compounds of Formula XXII

Preferred compounds of Formula XXII include those where R_(C) isC₁-C₆alkyl, C₃-C₇cycloalkyl, C₁-C₆ haloalkyl,C₃-C₇cycloalkyl(C₁-C₆)alkyl, or heterocycloalkyl.

More preferred compounds of Formula XXII include those where R_(C) isC₃-C₇cycloalkyl, C₁-C₆ haloalkyl, heterocycloalkyl, orC₃-C₇cycloalkyl(C₁-C₆)alkyl, and X₂ is carbon and R₅ and R₆ areC₁-C₆alkyl.

Particularly preferred compounds of Formula XXII include those whereR_(C) is C₁-C₃alkyl, C₃-C₅cycloalkyl, C₃-C₅cycloalkyl(C₁-C₃)alkyl, orC₁-C₂ haloalkyl.

Other particularly preferred compounds of Formula XXII include thosewhere R_(C) is methyl, ethyl, cyclopropyl, cyclopropylmethyl,perfluoropropyl, 2,2,2-trifluoroethyl, fluoromethyl, difluoromethyl,perfluoroethyl, or trifluoromethyl.

In a preferred aspect, the invention provides compounds formula I,wherein Q₃ is C—R₂₁.

In a more preferred aspect, the invention provides compounds formula I,wherein Q₃ is C—R₂₁, wherein R₂₁ is cyano.

In more preferred aspect, the invention provides compounds Formula XXIV,

In another preferred aspect, the invention provides compounds formula I,wherein X₁ is N.

In a more preferred aspect, the invention provides compounds formula I,wherein Q₃ is C—R₂₁, wherein R₂₁ is —C(O)OH, —C(O)—O(C₁-C₆ alkyl), or agroup of the formula,

In a another more preferred aspect, the invention provides compoundsformula I, wherein Q₃ is C—R₂₁, wherein R₂₁ is a group of the formula,

In a preferred aspect, the invention provides compounds formula XXV,

In a preferred aspect, the invention provides compounds formula XXV,wherein X₁ is N.

In a preferred aspect, the invention provides compounds formula XXV,wherein X₁ is N; and

R₃ and R₄ are independently hydrogen, halo, or —Z₁R_(Z1), wherein

-   -   Z₁ is —O— or —NH—;    -   R_(Z1) is a C₁-C₁₄ alkyl group where up to five of the carbon        atoms in the alkyl group are optionally replaced independently        by R₂₂, carbonyl, ethenyl, ethynyl or a moiety selected from N,        O, S, SO₂, or SO, with the proviso that two O atoms, two S        atoms, or an O and S atom are not immediately adjacent each        other,        -   wherein R_(Z1) is optionally substituted at any available            position with C₁-C₁₀ alkyl, C₁-C₁₀ haloalkyl, C₂-C₁₀            alkenyl, C₂-C₁₀ alkynyl, hydroxy, carboxy, carboxamido, oxo,            halo, amino, cyano, nitro, —SH, —S—(C₁-C₆)alkyl,            —SO₂—(C₁-C₆)alkyl, —SO₂NH₂, —SO₂NH—(C₁-C₆)alkyl,            —SO₂NH-aryl, —SO₂-aryl, —SO—(C₁-C₆)alkyl, —SO₂-aryl, C₁-C₆            alkoxy, C₂-C₁₀ alkenyloxy, C₂-C₁₀ alkynyloxy, mono- or            di-(C₁-C₁₀)alkylamino, —OC₁-C₁₀ alkyl-Z, or R₂₃.

In a preferred aspect, the invention provides compounds formula XXV,wherein X₁ is N; and

-   -   R₄ is H; and    -   R₃ hydrogen, halo, or —Z₁R_(Z1), wherein        -   Z₁ is —O— or —NH—;        -   R_(Z1) is a C₁-C₁₄ alkyl group where up to five of the            carbon atoms in the alkyl group are optionally replaced            independently by R₂₂, carbonyl, ethenyl, ethynyl or a moiety            selected from N, O, S, SO₂, or SO, with the proviso that two            O atoms, two S atoms, or an O and S atom are not immediately            adjacent each other,            -   wherein R_(Z1) is optionally substituted at any                available position with C₁-C₁₀ alkyl, C₁-C₁₀ haloalkyl,                C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, hydroxy, carboxy,                carboxamido, oxo, halo, amino, cyano, nitro, —SH,                —S—(C₁-C₆)alkyl, —SO₂—(C₁-C₆)alkyl, —SO₂NH₂,                —SO₂NH—(C₁-C₆)alkyl, —SO₂NH-aryl, —SO₂-aryl,                —SO—(C₁-C₆)alkyl, —SO₂-aryl, C₁-C₆ alkoxy, C₂-C₁₀                alkenyloxy, C₂-C₁₀ alkynyloxy, mono- or                di-(C₁-C₁₀)alkylamino, —OC₁-C₁₀ alkyl-Z, or R₂₃.

In a preferred aspect, the invention provides compounds formula XXV,wherein X₁ is N; and

-   -   R₄ is H; and    -   R₃ is —N(H)R_(Z1), wherein        -   R_(Z1) is a C₁-C₁₄ alkyl group where up to five of the            carbon atoms in the alkyl group are optionally replaced            independently by R₂₂, carbonyl, ethenyl, ethynyl or a moiety            selected from N, Or S, SO₂, or SO, with the proviso that two            O atoms, two S atoms, or an O and S atom are not immediately            adjacent each other,            -   wherein R_(Z1) is optionally substituted at any                available position with C₁-C₁₀ alkyl, C₁-C₁₀ haloalkyl,                C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, hydroxy, carboxy,                carboxamido, oxo, halo, amino, cyano, nitro, —SH,                —S—(C₁-C₆)alkyl, —SO₂—(C₁-C₆)alkyl, —SO₂NH₂,                —SO₂NH—(C₁-C₆)alkyl, —SO₂NH-aryl, —SO₂-aryl,                —SO—(C₁-C₆)alkyl, —SO₂-aryl, C₁-C₆ alkoxy, C₂-C₁₀                alkenyloxy, C₂-C₁₀ alkynyloxy, mono- or                di-(C₁-C₁₀)alkylamino, —OC₁-C₁₀ alkyl-Z, or R₂₃.

In a preferred aspect, the invention provides compounds formula XXV,wherein X₁ is N;

-   -   R₄ is H;    -   R₃ is —N(H)R_(Z1), wherein        -   R_(Z1) is a C₁-C₁₄ alkyl group where up to five of the            carbon atoms in the alkyl group are optionally replaced            independently by R₂₂, carbonyl, ethenyl, ethynyl or a moiety            selected from N, O, S, SO₂, or SO, with the proviso that two            O atoms, two S atoms, or an O and S atom are not immediately            adjacent each other,            -   wherein R_(Z1) is optionally substituted at any                available position with C₁-C₁₀ alkyl, C₁-C₁₀ haloalkyl,                C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, hydroxy, carboxy,                carboxamido, oxo, halo, amino, cyano, nitro, —SH,                —S—(C₁-C₆)alkyl, —SO₂—(C₁-C₆)alkyl, —SO₂NH₂,                —SO₂NH—(C₁-C₆)alkyl, —SO₂NH-aryl, —SO₂-aryl,                —SO—(C₁-C₆)alkyl, —SO₂-aryl, C₁-C₆ alkoxy, C₂-C₁₀                alkenyloxy, C₂-C₁₀ alkynyloxy, mono- or                di-(C₁-C₁₀)alkylamino, —OC₁-C₁₀ alkyl-Z, or R₂₃; and    -   R_(C) is methyl, ethyl, cyclopropyl, cyclopropylmethyl,        fluoromethyl, difluoromethyl, or trifluoromethyl.

In a preferred aspect, the invention provides compounds formula XXV,wherein X₁ is N; and

-   -   R₃ is H; and    -   R₄ is hydrogen, halo, or —Z₁R_(Z1), wherein        -   Z₁ is —O— or —NH—;        -   R_(Z1) is a C₁-C₁₄ alkyl group where up to five of the            carbon atoms in the alkyl group are optionally replaced            independently by R₂₂, carbonyl, ethenyl, ethynyl or a moiety            selected from N, O, S, SO₂, or SO, with the proviso that two            O atoms, two S atoms, or an O and S atom are not immediately            adjacent each other,            -   wherein R_(Z1) is optionally substituted at any                available position with C₁-C₁₀ alkyl, C₁-C₁₀ haloalkyl,                C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, hydroxy, carboxy,                carboxamido, oxo, halo, amino, cyano, nitro, —SH,                —S—(C₁-C₆)alkyl, —SO₂—(C₁-C₆)alkyl, —SO₂NH₂,                —SO₂NH—(C₁-C₆)alkyl, —SO₂NH-aryl, —SO₂-aryl,                —SO—(C₁-C₆)alkyl, —SO₂-aryl, C₁-C₆ alkoxy, C₂-C₁₀                alkenyloxy, C₂-C₁₀ alkynyloxy, mono- or                di-(C₁-C₁₀)alkylamino, —OC₁-C₁₀ alkyl-Z, or R₂₃.

In a preferred aspect, the invention provides compounds formula XXV,wherein X₁ is N;

-   -   R₃ is H;    -   R₄ is hydrogen, halo, or —Z₁R_(Z1), wherein        -   Z₁ is —O— or —NH—;        -   R_(Z1) is a C₁-C₁₄ alkyl group where up to five of the            carbon atoms in the alkyl group are optionally replaced            independently by R₂₂, carbonyl, ethenyl, ethynyl or a moiety            selected from N, O, S, SO₂, or SO, with the proviso that two            O atoms, two S atoms, or an O and S atom are not immediately            adjacent each other,            -   wherein R_(Z1) is optionally substituted at any                available position with C₁-C₁₀ alkyl, C₁-C₁₀ haloalkyl,                C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, hydroxy, carboxy,                carboxamido, oxo, halo, amino, cyano, nitro, —SH,                —S—(C₁-C₆)alkyl, —SO₂—(C₁-C₆)alkyl, —SO₂NH₂,                —SO₂NH—(C₁-C₆)alkyl, —SO₂NH-aryl, —SO₂-aryl,                —SO—(C₁-C₆)alkyl, —SO₂-aryl, C₁-C₆ alkoxy, C₂-C₁₀                alkenyloxy, C₂-C₁₀ alkynyloxy, mono- or                di-(C₁-C₁₀)alkylamino, —OC₁-C₁₀ alkyl-Z, or R₂₃; and    -   R_(C) is methyl, ethyl, cyclopropyl, cyclopropylmethyl,        fluoromethyl, difluoromethyl, or trifluoromethyl.

In a preferred aspect, the invention provides compounds formula XXV,wherein

-   -   X₁ is CR₁₁, wherein    -   R₁₁ is hydrogen, halogen, cyano, nitro, —C(O)R_(C′), C₁-C₁₀        alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₁-C₁₀ haloalkyl, C₃-C₇        cycloalkyl, C₃-C₇ cycloalkyl(C₁-C₁₀)alkyl, heterocycloalkyl,        aryl, or heteroaryl, wherein        -   R_(C′) is —C₁-C₆ alkyl, —OR_(C″), or —N(R_(CN))₂, wherein            -   R_(C″) is —H, C₁-C₁₀ alkyl, C₁-C₁₀ haloalkyl, C₃-C₇                cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;            -   each R_(CN) is independently —H, —C₁-C₁₀ alkyl,                —C₁-C₁₀-haloalkyl, —C₃-C₇ cycloalkyl, -heterocycloalkyl,                —C₁-C₆ acyl, -aryl, or -heteroaryl.

In a more preferred aspect, the invention provides compounds formulaXXV, wherein

-   -   X₁ is CR₁₁, wherein        -   R₁₁ is hydrogen, halogen, C₁-C₁₀ alkyl, C₁-C₁₀ haloalkyl,            C₃-C₇ cycloalkyl, C₃-C₇ cycloalkyl(C₁-C₁₀)alkyl, aryl, or            heteroaryl.

In a preferred aspect, the invention provides compounds formula XXV,wherein

-   -   X₁ is CR₁₁, wherein    -   R₁₁ is hydrogen, halogen, cyano, nitro, —C(O)R_(C′), C₁-C₁₀        alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₁-C₁₀ haloalkyl, C₃-C₇        cycloalkyl, C₃-C₇ cycloalkyl(C₁-C₁₀)alkyl, heterocycloalkyl,        aryl, or heteroaryl, wherein        -   R_(C′) is —C₁-C₆ alkyl, —OR_(C″), or —N(R_(CN))₂, wherein            -   R_(C″) is —H, C₁-C₁₀ alkyl, C₁-C₁₀ haloalkyl, C₃-C₇                cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;            -   each R_(CN) is independently —H, —C₁-C₁₀ alkyl,                —C₁-C₁₀-haloalkyl, —C₃-C₇ cycloalkyl, -heterocycloalkyl,                —C₁-C₆ acyl, -aryl, or heteroaryl; and    -   R₃ and R₄ are independently hydrogen, halo, or —Z₁R_(Z1),        wherein        -   Z₁ is —O— or —NH—;        -   R_(Z1) is a C₁-C₁₄ alkyl group where up to five of the            carbon atoms in the alkyl group are optionally replaced            independently by R₂₂, carbonyl, ethenyl, ethynyl or a moiety            selected from N, O, S, SO₂, or SO, with the proviso that two            O atoms, two S atoms, or an O and S atom are not immediately            adjacent each other,            -   wherein R_(Z1) is optionally substituted at any                available position with C₁-C₁₀ alkyl, C₁-C₁₀ haloalkyl,                C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, hydroxy, carboxy,                carboxamido, oxo, halo, amino, cyano, nitro, —SH,                —S—(C₁-C₆)alkyl, —SO₂—(C₁-C₆)alkyl, —SO₂NH₂,                —SO₂NH—(C₁-C₆)alkyl, —SO₂NH-aryl, —SO₂-aryl,                —SO—(C₁-C₆)alkyl, —SO₂-aryl, C₁-C₆ alkoxy, C₂-C₁₀                alkenyloxy, C₂-C₁₀ alkynyloxy, mono- or                di-(C₁-C₁₀)alkylamino, —OC₁-C₁₀ alkyl-Z, or R₂₃.

In a preferred aspect, the invention provides compounds formula XXV,wherein

-   -   X₁ is CR₁₁, wherein    -   R₁₁ is hydrogen, halogen, cyano, nitro, —C(O)R_(C′), C₁-C₁₀        alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₁-C₁₀ haloalkyl, C₃-C₇        cycloalkyl, C₃-C₇ cycloalkyl(C₁-C₁₀)alkyl, heterocycloalkyl,        aryl, or heteroaryl, wherein        -   R_(C′) is —C₁-C₆ alkyl, —OR_(C″), or —N(R_(CN))₂, wherein            -   R_(C″) is —H, C₁-C₁₀ alkyl, C₁-C₁₀ haloalkyl, C₃-C₇                cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;            -   each R_(CN) is independently —H, —C₁-C₁₀ alkyl,                —C₁-C₁₀-haloalkyl, —C₃-C₇ cycloalkyl, -heterocycloalkyl,                —C₁-C₆ acyl, -aryl, or -heteroaryl;    -   R₄ is H; and    -   R₃ hydrogen, halo, or —Z₁R_(Z1), wherein        -   Z₁ is —O— or —NH—;        -   R_(Z1) is a C₁-C₁₄ alkyl group where up to five of the            carbon atoms in the alkyl group are optionally replaced            independently by R₂₂, carbonyl, ethenyl, ethynyl or a moiety            selected from N, O, S, SO₂, or SO, with the proviso that two            O atoms, two S atoms, or an O and S atom are not immediately            adjacent each other,            -   wherein R_(Z1) is optionally substituted at any                available position with C₁-C₁₀ alkyl, C₁-C₁₀ haloalkyl,                C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, hydroxy, carboxy,                carboxamido, oxo, halo, amino, cyano, nitro, —SH,                —S—(C₁-C₆)alkyl, —SO₂—(C₁-C₆)alkyl, —SO₂NH₂,                —SO₂NH—(C₁-C₆)alkyl, —SO₂NH-aryl, —SO₂-aryl,                —SO—(C₁-C₆)alkyl, —SO₂-aryl, C₁-C₆ alkoxy, C₂-C₁₀                alkenyloxy, C₂-C₁₀ alkynyloxy, mono- or                di-(C₁-C₁₀)alkylamino, —OC₁-C₁₀ alkyl-Z, or R₂₃.

In a preferred aspect, the invention provides compounds formula XXV,wherein

-   -   X₁ is CR₁₁, wherein    -   R₁₁ is hydrogen, halogen, cyano, nitro, —C(O)R_(C′), C₁-C₁₀        alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₁-C₁₀ haloalkyl, C₃-C₇        cycloalkyl, C₃-C₇ cycloalkyl(C₁-C₁₀)alkyl, heterocycloalkyl,        aryl, or heteroaryl, wherein        -   R_(C′) is —C₁-C₆ alkyl, —OR_(C″), or —N(R_(CN))₂, wherein            -   R_(C″) is —H, C₁-C₁₀ alkyl, C₁-C₁₀ haloalkyl, C₃-C₇                cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;            -   each R_(CN) is independently —H, —C₁-C₁₀ alkyl,                —C₁-C₁₀-haloalkyl, —C₃-C₇ cycloalkyl, -heterocycloalkyl,                —C₁-C₆ acyl, -aryl, or -heteroaryl;    -   R₄ is H; and    -   R₃ is —N(H)R_(Z1), wherein        -   R_(Z1) is a C₁-C₁₄ alkyl group where up to five of the            carbon atoms in the alkyl group are optionally replaced            independently by R₂₂, carbonyl, ethenyl, ethynyl or a moiety            selected from N, O, S, SO₂, or SO, with the proviso that two            O atoms, two S atoms, or an O and S atom are not immediately            adjacent each other,            -   wherein R_(Z1) is optionally substituted at any                available position with C₁-C₁₀ alkyl, C₁-C₁₀ haloalkyl,                C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, hydroxy, carboxy,                carboxamido, oxo, halo, amino, cyano, nitro, —SH,                —S—(C₁-C₆)alkyl, —SO₂—(C₁-C₆)alkyl, —SO₂NH₂,                —SO₂NH—(C₁-C₆)alkyl, —SO₂NH-aryl, —SO₂-aryl,                —SO—(C₁-C₆)alkyl, —SO₂-aryl, C₁-C₆ alkoxy, C₂-C₁₀                alkenyloxy, C₂-C₁₀ alkynyloxy, mono- or                di-(C₁-C₁₀)alkylamino, —OC₁-C₁₀ alkyl-Z, or R₂₃.

In a preferred aspect, the invention provides compounds formula XXV,wherein

-   -   X₁ is CR₁₁, wherein    -   R₁₁ is hydrogen, halogen, cyano, nitro, —C(O)R_(C′), C₁-C₁₀        alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₁-C₁₀ haloalkyl, C₃-C₇        cycloalkyl, C₃-C₇ cycloalkyl(C₁-C₁₀)alkyl, heterocycloalkyl,        aryl, or heteroaryl, wherein        -   R_(C′) is —C₁-C₆ alkyl, —OR_(C″), or —N(R_(CN))₂, wherein            -   R_(C″) is —H, C₁-C₁₀ alkyl, C₁-C₁₀ haloalkyl, C₃-C₇                cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;            -   each R_(CN) is independently —H, —C₁-C₁₀ alkyl,                —C₁-C₁₀-haloalkyl, —C₃-C₇ cycloalkyl, -heterocycloalkyl,                —C₁-C₆ acyl, -aryl, or -heteroaryl;    -   R₄ is H;    -   R₃ is —N(H)R_(Z1), wherein        -   R_(Z1) is a C₁-C₁₄ alkyl group where up to five of the            carbon atoms in the alkyl group are optionally replaced            independently by R₂₂, carbonyl, ethenyl, ethynyl or a moiety            selected from N, O, S, SO₂, or SO, with the proviso that two            O atoms, two S atoms, or an O and S atom are not immediately            adjacent each other,            -   wherein R_(Z1) is optionally substituted at any                available position with C₁-C₁₀ alkyl, C₁-C₁₀ haloalkyl,                C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, hydroxy, carboxy,                carboxamido, oxo, halo, amino, cyano, nitro, —SH,                —S—(C₁-C₆)alkyl, —SO₂—(C₁-C₆)alkyl, —SO₂NH₂,                —SO₂NH—(C₁-C₆)alkyl, —SO₂NH-aryl, —SO₂-aryl,                —SO—(C₁-C₆)alkyl, —SO₂-aryl, C₁-C₆ alkoxy, C₂-C₁₀                alkenyloxy, C₂-C₁₀ alkynyloxy, mono- or                di-(C₁-C₁₀)alkylamino, —OC₁-C₁₀ alkyl-Z, or R₂₃; and    -   R_(C) is hydrogen, methyl, ethyl, cyclopropyl,        cyclopropylmethyl, fluoromethyl, difluoromethyl, or        trifluoromethyl.

In a preferred aspect, the invention provides compounds formula XXV,wherein

-   -   X₁ is CR₁₁, wherein    -   R₁₁ is hydrogen, halogen, cyano, nitro, —C(O)R_(C′), C₁-C₁₀        alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₁-C₁₀ haloalkyl, C₃-C₇        cycloalkyl, C₃-C₇ cycloalkyl(C₁-C₁₀)alkyl, heterocycloalkyl,        aryl, or heteroaryl, wherein        -   R_(C′) is —C₁-C₆ alkyl, —OR_(C″), or —N(R_(CN))₂, wherein            -   R_(C″) is —H, C₁-C₁₀ alkyl, C₁-C₁₀ haloalkyl, C₃-C₇                cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;            -   each R_(CN) is independently —H, —C₁-C₁₀ alkyl,                —C₁-C₁₀-haloalkyl, —C₃-C₇ cycloalkyl, -heterocycloalkyl,                —C₁-C₆ acyl, -aryl, or -heteroaryl;    -   R₃ is H; and    -   R₄ is hydrogen, halo, or —Z₁R_(Z1), wherein        -   Z₁ is —O— or —NH—;        -   R_(Z1) is a C₁-C₁₄ alkyl group where up to five of the            carbon atoms in the alkyl group are optionally replaced            independently by R₂₂, carbonyl, ethenyl, ethynyl or a moiety            selected from N, O, S, SO₂, or SO, with the proviso that two            O atoms, two S atoms, or an O and S atom are not immediately            adjacent each other,            -   wherein R_(Z1) is optionally substituted at any                available position with C₁-C₁₀ alkyl, C₁-C₁₀ haloalkyl,                C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, hydroxy, carboxy,                carboxamido, oxo, halo, amino, cyano, nitro, —SH,                —S—(C₁-C₆)alkyl, —SO₂—(C₁-C₆)alkyl, —SO₂NH₂,                —SO₂NH—(C₁-C₆)alkyl, —SO₂NH-aryl, —SO₂-aryl,                —SO—(C₁-C₆)alkyl, —SO₂-aryl, C₁-C₆ alkoxy, C₂-C₁₀                alkenyloxy, C₂-C₁₀ alkynyloxy, mono- or                di-(C₁-C₁₀)alkylamino, —OC₁-C₁₀ alkyl-Z, or R₂₃.

In a preferred aspect, the invention provides compounds formula XXV,wherein

-   -   X₁ is CR₁₁, wherein    -   R₁₁ is hydrogen, halogen, cyano, nitro, —C(O)R_(C′), C₁-C₁₀        alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₁-C₁₀ haloalkyl, C₃-C₇        cycloalkyl, C₃-C₇ cycloalkyl(C₁-C₁₀)alkyl, heterocycloalkyl,        aryl, or heteroaryl, wherein        -   R_(C′) is —C₁-C₆ alkyl, —OR_(C″), or —N(R_(CN))₂, wherein            -   R_(C″) is —H, C₁-C₁₀ alkyl, C₁-C₁₀ haloalkyl, C₃-C₇                cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;            -   each R_(CN) is independently —H, —C₁-C₁₀ alkyl,                —C₁-C₁₀-haloalkyl, —C₃-C₇ cycloalkyl, -heterocycloalkyl,                —C₁-C₆ acyl, -aryl, or -heteroaryl;    -   R₃ is H;    -   R₄ is hydrogen, halo, or —Z₁R_(Z1), wherein        -   Z₁ is —O— or —NH—;        -   R_(Z1) is a C₁-C₁₄ alkyl group where up to five of the            carbon atoms in the alkyl group are optionally replaced            independently by R₂₂, carbonyl, ethenyl, ethynyl or a moiety            selected from N, O, S, SO₂, or SO, with the proviso that two            O atoms, two S atoms, or an O and S atom are not immediately            adjacent each other,            -   wherein R_(Z1) is optionally substituted at any                available position with C₁-C₁₀ alkyl, C₁-C₁₀ haloalkyl,                C₂-C₁₀ alkenyl, C₂-C₁₀alkynyl, hydroxy, carboxy,                carboxamido, oxo, halo, amino, cyano, nitro, —SH,                —S—(C₁-C₆)alkyl, —SO₂—(C₁-C₆)alkyl, —SO₂NH₂,                —SO₂NH—(C₁-C₆)alkyl, —SO₂NH-aryl, —SO₂-aryl,                —SO—(C₁-C₆)alkyl, —SO₂-aryl, C₁-C₆ alkoxy, C₂-C₁₀                alkenyloxy, C₂-C₁₀ alkynyloxy, mono- or                di-(C₁-C₁₀)alkylamino, —OC₁-C₁₀ alkyl-Z, or R₂₃; and    -   R_(C) is hydrogen, methyl, ethyl, cyclopropyl,        cyclopropylmethyl, fluoromethyl, difluoromethyl, or        trifluoromethyl.

In another aspect, the invention encompasses a method of treating cancercomprising administering to a patient in need thereof, apharmaceutically acceptable amount of a compound or salt of Formula I ora pharmaceutical composition comprising a compound or salt of Formula I.

In another aspect, the invention encompasses the use of atherapeutically effective amount of a compound or salt of Formula I forthe preparation of a medicament for the treatment of cancer,inflammation, or arthritis in a patient in need of such treatment.

In another aspect, the invention encompasses a package comprising acompound or salt of Formula I in a container with instructions on how touse the compound.

In another aspect, the invention encompasses the use of atherapeutically effective amount of a compound or salt according ofFormula I for the preparation of a medicament for the treatment of adisease or condition related to cell proliferation in a patient in needof such treatment.

In another aspect, the invention encompasses the use of atherapeutically effective amount of a compound or salt according ofFormula I for the preparation of a medicament for the treatment of adisease or condition related to cell proliferation in a patient in needof such treatment, wherein the disease or condition is cancer,inflammation, or arthritis.

In another aspect, the invention encompasses the use of therapeuticallyeffective amount of a compound or salt of Formula I for the preparationof a medicament for the treatment of a disease or disorder related tothe activity of heat shock protein 90, in a subject in need of such.

In another aspect, the invention encompasses the use of therapeuticallyeffective amount of a compound or salt of Formula I, alone or incombination with another therapeutic agent, for the preparation of amedicament for the treatment of a disease or disorder related to theactivity of heat shock protein 90 and/or its client proteins, in asubject in need of such, wherein the HSP-90 mediated disorder isselected from the group of inflammatory diseases, infections, autoimmunedisorders, stroke, ischemia, cardiac disorders, neurological disorders,fibrogenetic disorders, proliferative disorders, tumors, leukemias,neoplasms, cancers, carcinomas, metabolic diseases and malignantdisease.

In a preferred aspect, the invention encompasses methods for thetreatment of cancer in a subject in need of such treatment comprisingadministration of therapeutically effective amount of a compound or saltof Formula I, in combination with at least one other therapeutic agent.

In a more preferred aspect, the invention encompasses methods fortreating cancer in a subject in need of such treatment, the methodscomprising administration of therapeutically effective amount of acompound or salt of Formula I, in combination with at least one otheranti-cancer agent.

In another preferred aspect, the invention encompasses methods fortreating cancer, the methods comprising administration, to a subject inneed of such treatment, of a therapeutically effective amount of acompound or salt of Formula I, in combination with radiation therapy.

In another aspect, the invention encompasses the use of therapeuticallyeffective amount of a compound or salt of Formula I for the preparationof a medicament for the treatment of a fibrogenetic disorder related tothe activity of heat shock protein 90, in a subject in need of such,wherein the fibrogenetic disorder is selected from the group ofscleroderma, polymyositis, systemic lupus, rheumatoid arthritis, livercirrhosis, keloid formation, interstitial nephritis and pulmonaryfibrosis.

In another aspect, the invention encompasses the use of atherapeutically effective amount of a compound or salt of Formula I forthe preparation of a medicament for protecting a subject from infectioncaused by an organism selected from Plasmodium species.

In a preferred aspect, the invention encompasses the use of atherapeutically effective amount of a compound or salt of Formula I forthe preparation of a medicament for protecting a subject from infectioncaused by Plasmodium falciparum.

In another aspect, the invention encompasses the use of atherapeutically effective amount of a compound or salt of Formula I forthe preparation of a medicament for reducing the level of infectioncaused by an organism selected from Plasmodium species in a subject inneed of such treatment.

In a preferred aspect, the invention encompasses the use of atherapeutically effective amount of a compound or salt of Formula I forthe preparation of a medicament for reducing the level of infectioncaused by Plasmodium falciparum in a subject in need of such treatment.

In another aspect, the invention encompasses the use of atherapeutically effective amount of a compound or salt of Formula I forthe preparation of a medicament for treating a patient infected with ametazoan parasite.

In a preferred aspect, the invention encompasses the use of atherapeutically effective amount of a compound or salt of Formula I forthe preparation of a medicament for treating a patient infected by ametazoan parasite which is Plasmodium falciparum.

In another aspect, the invention encompasses the use of atherapeutically effective amount of a compound or salt of Formula I incombination with one or more known anti-fungal drugs for the preparationof a medicament for treating a patient infected with a fungal infection.

DEFINITIONS

The term “alkoxy” represents an alkyl group of indicated number ofcarbon atoms attached to the parent molecular moiety through an oxygenbridge. Examples of alkoxy groups include, for example, methoxy, ethoxy,propoxy and isopropoxy.

As used herein, the term “alkyl” includes those alkyl groups of adesignated number of carbon atoms. Alkyl groups may be straight, orbranched. Examples of “alkyl” include methyl, ethyl, propyl, isopropyl,butyl, iso-, sec- and tert-butyl, pentyl, hexyl, heptyl, 3-ethylbutyl,and the like.

The term “alkenyl” as used herein, means a straight or branched chainhydrocarbon containing from 2 to 10 carbons and containing at least onecarbon-carbon double bond formed by the removal of two hydrogens.Representative examples of alkenyl include, but are not limited to,ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl,5-hexenyl, 2-heptenyl, 2-methyl-1-heptenyl, and 3-decenyl.

The term “alkenoxy” refers to an alkenyl group attached to the parentgroup through an oxygen atom.

The term “alkynyl” as used herein, means a straight or branched chainhydrocarbon group containing from 2 to 10 carbon atoms and containing atleast one carbon-carbon triple bond. Representative examples of alkynylinclude, but are not limited, to acetylenyl, 1-propynyl, 2-propynyl,3-butynyl, 2-pentynyl, and 1-butynyl.

The term “aryl” refers to an aromatic hydrocarbon ring system containingat least one aromatic ring. The aromatic ring may optionally be fused orotherwise attached to other aromatic hydrocarbon rings or non-aromatichydrocarbon rings. Examples of aryl groups include, for example, phenyl,naphthyl, 1,2,3,4-tetrahydronaphthalene and biphenyl. Preferred examplesof aryl groups include phenyl, naphthyl, and anthracenyl. More preferredaryl groups are phenyl and naphthyl. Most preferred is phenyl. The arylgroups of the invention may be substituted with various groups asprovided herein. Thus, any carbon atom present within an aryl ringsystem and available for substitution may be further bonded to a varietyof ring substituents, such as, for example, halogen, hydroxy, nitro,cyano, amino, C₁-C₈alkyl, C₁-C₈alkoxy, mono- and di(C₁-C₈alkyl)amino,C₃-C₁₀cycloalkyl, (C₃-C₁₀cycloalkyl)alkyl, (C₃-C₁₀cycloalkyl)alkoxy,C₂-C₉heterocycloalkyl, C₁-C₈alkenyl, C₁-C₈alkynyl, halo(C₁-C₈)alkyl,halo(C₁-C₈)alkoxy, oxo, amino(C₁-C₈)alkyl, mono- anddi(C₁-C₈alkyl)amino(C₁-C₈)alkyl, C₁-C₈acyl, C₁-C₈acyloxy, C₁-C₈sulfonyl,C₁-C₈thio, C₁-C₈sulfonamido, C₁-C₈-aminosulfonyl.

The term “carboxy” as used herein, means a —CO₂H group.

The term “cycloalkyl” refers to a C₃-C₈ cyclic hydrocarbon. Examples ofcycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl and cyclooctyl. More preferred are C₃-C₆ cycloalkyl groups.The cycloalkyl groups of the invention may be substituted with variousgroups as provided herein. Thus, any carbon atom present within acycloalkyl ring system and available for substitution may be furtherbonded to a variety of ring substituents, such as, for example, halogen,hydroxy, nitro, cyano, amino, C₁-C₈alkyl, C₁-C₈alkoxy, mono- anddi(C₁-C₈alkyl)amino, C₃-C₁₀cycloalkyl, (C₃-C₁₀cycloalkyl)alkyl,(C₃-C₁₀cycloalkyl)alkoxy, C₂-C₉heterocycloalkyl, C₁-C₈alkenyl,C₁-C₈alkynyl, halo(C₁-C₈)alkyl, halo(C₁-C₈)alkoxy, oxo,amino(C₁-C₈)alkyl and mono- and di(C₁-C₈alkyl)amino(C₁-C₈)alkyl.

The terms “halogen” or “halo” indicate fluorine, chlorine, bromine, andiodine.

The term “haloalkoxy” refers to an alkoxy group substituted with one ormore halogen atoms, where each halogen is independently F, Cl, Br or I.Preferred halogens are F and Cl. Preferred haloalkoxy groups contain 1-6carbons, more preferably 1-4 carbons, and still more preferably 1-2carbons. “Haloalkoxy” includes perhaloalkoxy groups, such as OCF₃ orOCF₂CF₃. A preferred haloalkoxy group is trifluoromethoxy.

The term “haloalkyl” refers to an alkyl group substituted with one ormore halogen atoms, where each halogen is independently F, Cl, Br or I.Preferred halogens are F and Cl. Preferred haloalkyl groups contain 1-6carbons, more preferably 1-4 carbons, and still more preferably 1-2carbons. “Haloalkyl” includes perhaloalkyl groups, such as CF₃ orCF₂CF₃. A preferred haloalkyl group is trifluoromethyl.

The term “heterocycloalkyl” refers to a ring or ring system containingat least one heteroatom selected from nitrogen, oxygen, and sulfur,wherein said heteroatom is in a non-aromatic ring. The heterocycloalkylring is optionally fused to or otherwise attached to otherheterocycloalkyl rings and/or non-aromatic hydrocarbon rings and/orphenyl rings. Preferred heterocycloalkyl groups have from 3 to 7members. More preferred heterocycloalkyl groups have 5 or 6 members.Examples of heterocycloalkyl groups include, for example,1,2,3,4-tetrahydroisoquinolinyl, piperazinyl, morpholinyl, piperidinyl,tetrahydrofuranyl, pyrrolidinyl, pyridinonyl, and pyrazolidinyl.Preferred heterocycloalkyl groups include piperidinyl, piperazinyl,morpholinyl, pyrrolidinyl, pyridinonyl, dihydropyrrolidinyl, andpyrrolidinonyl. The heterocycloalkyl groups of the invention may besubstituted with various groups as provided herein. Thus, any atompresent within a heterocycloalkyl ring and available for substitutionmay be further bonded to a variety of ring substituents, such as, forexample, halogen, hydroxy, nitro, cyano, amino, C₁-C₈alkyl, C₁-C₈alkoxy,mono- and di(C₁-C₈alkyl)amino, C₃-C₁₀cycloalkyl,(C₃-C₁₀cycloalkyl)alkyl, (C₃-C₁₀cycloalkyl)alkoxy,C₂-C₉heterocycloalkyl, C₁-C₈alkenyl, C₁-C₈alkynyl, halo(C₁-C₈)alkyl,halo(C₁-C₈)alkoxy, oxo, amino(C₁-C₈)alkyl and mono- anddi(C₁-C₈alkyl)amino(C₁-C₈)alkyl.

The term “heteroaryl” refers to an aromatic ring system containing atleast one heteroatom selected from nitrogen, oxygen, and sulfur. Theheteroaryl ring may be fused or otherwise attached to one or moreheteroaryl rings, aromatic or non-aromatic hydrocarbon rings orheterocycloalkyl rings. Examples of heteroaryl groups include, forexample, pyridine, furan, thienyl, 5,6,7,8-tetrahydroisoquinoline andpyrimidines. The heteroaryl groups of the invention may be substitutedwith various groups as provided herein. Thus, any carbon atom presentwithin an heteroaryl ring system and available for substitution may befurther bonded to a variety of ring substituents, such as, for example,halogen, hydroxy, nitro, cyano, amino, C₁-C₈alkyl, C₁-C₈alkoxy, mono-and di(C₁-C₈alkyl)amino, C₃-C₁₀cycloalkyl, (C₃-C₁₀cycloalkyl)alkyl,(C₃-C₁₀cycloalkyl)alkoxy, C₂-C₉heterocycloalkyl, C₁-C₈alkenyl,C₁-C₈alkynyl, halo(C₁-C₈)alkyl, halo(C₁-C₈)alkoxy, oxo,amino(C₁-C₈)alkyl and mono- and di(C₁-C₈alkyl)amino(C₁-C₈)alkyl.

Preferred examples of heteroaryl groups include thienyl, benzothienyl,pyridyl, quinolyl, pyrazolyl, pyrimidyl, imidazolyl, benzimidazolyl,furanyl, benzofuranyl, dibenzofuranyl, thiazolyl, benzothiazolyl,isoxazolyl, oxadiazolyl, isothiazolyl, benzisothiazolyl, triazolyl,pyrrolyl, indolyl, pyrazolyl, and benzopyrazolyl.

The compounds of this invention may contain one or more asymmetriccarbon atoms, so that the compounds can exist in differentstereoisomeric forms. These compounds can be, for example, racemates,chiral non-racemic or diastereomers. In these situations, the singleenantiomers, i.e., optically active forms, can be obtained by asymmetricsynthesis or by resolution of the racemates. Resolution of the racematescan be accomplished, for example, by conventional methods such ascrystallization in the presence of a resolving agent; chromatography,using, for example a chiral HPLC column; or derivatizing the racemicmixture with a resolving reagent to generate diastereomers, separatingthe diastereomers via chromatography, and removing the resolving agentto generate the original compound in enantiomerically enriched form. Anyof the above procedures can be repeated to increase the enantiomericpurity of a compound.

When the compounds described herein contain olefinic double bonds orother centers of geometric asymmetry, and unless otherwise specified, itis intended that the compounds include the cis, trans, Z- andE-configurations. Likewise, all tautomeric forms are also intended to beincluded.

Pharmaceutical Compositions

The compounds of general Formula I may be administered orally,topically, parenterally, by inhalation or spray or rectally in dosageunit formulations containing conventional non-toxic pharmaceuticallyacceptable carriers, adjuvants and vehicles. The term parenteral as usedherein includes percutaneous, subcutaneous, intravascular (e.g.,intravenous), intramuscular, or intrathecal injection or infusiontechniques and the like. In addition, there is provided a pharmaceuticalformulation comprising a compound of general Formula I and apharmaceutically acceptable carrier. One or more compounds of generalFormula I may be present in association with one or more non-toxicpharmaceutically acceptable carriers and/or diluents and/or adjuvants,and if desired other active ingredients. The pharmaceutical compositionscontaining compounds of general Formula I may be in a form suitable fororal use, for example, as tablets, troches, lozenges, aqueous or oilysuspensions, dispersible powders or granules, emulsion, hard or softcapsules, or syrups or elixirs.

Compositions intended for oral use may be prepared according to anymethod known in the art for the manufacture of pharmaceuticalcompositions and such compositions may contain one or more agentsselected from the group consisting of sweetening agents, flavoringagents, coloring agents and preservative agents in order to providepharmaceutically elegant and palatable preparations. Tablets contain theactive ingredient in admixture with non-toxic pharmaceuticallyacceptable excipients that are suitable for the manufacture of tablets.These excipients may be for example, inert diluents, such as calciumcarbonate, sodium carbonate, lactose, calcium phosphate or sodiumphosphate; granulating and disintegrating agents, for example, cornstarch, or alginic acid; binding agents, for example starch, gelatin oracacia, and lubricating agents, for example magnesium stearate, stearicacid or talc. The tablets may be uncoated or they may be coated by knowntechniques. In some cases such coatings may be prepared by knowntechniques to delay disintegration and absorption in thegastrointestinal tract and thereby provide a sustained action over alonger period. For example, a time delay material such as glycerylmonosterate or glyceryl distearate may be employed.

Formulations for oral use may also be presented as hard gelatincapsules, wherein the active ingredient is mixed with an inert soliddiluent, for example, calcium carbonate, calcium phosphate or kaolin, oras soft gelatin capsules wherein the active ingredient is mixed withwater or an oil medium, for example peanut oil, liquid paraffin or oliveoil.

Formulations for oral use may also be presented as lozenges.

Aqueous suspensions contain the active materials in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydropropyl-methylcellulose,sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally-occurring phosphatide,for example, lecithin, or condensation products of an alkylene oxidewith fatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethyleneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan monooleate.The aqueous suspensions may also contain one or more preservatives, forexample ethyl, or n-propyl p-hydroxybenzoate, one or more coloringagents, one or more flavoring agents, and one or more sweetening agents,such as sucrose or saccharin.

Oily suspensions may be formulated by suspending the active ingredientsin a vegetable oil, for example arachis oil, olive oil, sesame oil orcoconut oil, or in a mineral oil such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example beeswax, hardparaffin or cetyl alcohol. Sweetening agents and flavoring agents may beadded to provide palatable oral preparations. These compositions may bepreserved by the addition of an anti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents orsuspending agents are exemplified by those already mentioned above.Additional excipients, for example sweetening, flavoring and coloringagents, may also be present.

Pharmaceutical compositions of the invention may also be in the form ofoil-in-water emulsions. The oily phase may be a vegetable oil or amineral oil or mixtures of these. Suitable emulsifying agents may benaturally-occurring gums, for example gum acacia or gum tragacanth,naturally-occurring phosphatides, for example soy bean, lecithin, andesters or partial esters derived from fatty acids and hexitol,anhydrides, for example sorbitan monooleate, and condensation productsof the said partial esters with ethylene oxide, for examplepolyoxyethylene sorbitan monooleate. The emulsions may also containsweetening and flavoring agents.

Syrups and elixirs may be formulated with sweetening agents, for exampleglycerol, propylene glycol, sorbitol, glucose or sucrose. Suchformulations may also contain a demulcent, a preservative and flavoringand coloring agents. The pharmaceutical compositions may be in the formof a sterile injectable aqueous or oleaginous suspension. Thissuspension may be formulated according to the known art using thosesuitable dispersing or wetting agents and suspending agents that havebeen mentioned above. The sterile injectable preparation may also be asterile injectable solution or suspension in a non-toxic parentallyacceptable diluent or solvent, for example as a solution in1,3-butanediol. Among the acceptable vehicles and solvents that may beemployed are water, Ringer's solution and isotonic sodium chloridesolution. In addition, sterile, fixed oils are conventionally employedas a solvent or suspending medium. For this purpose any bland fixed oilmay be employed including synthetic mono- or diglycerides. In addition,fatty acids such as oleic acid find use in the preparation ofinjectables.

The compounds of general Formula I may also be administered in the formof suppositories, e.g., for rectal administration of the drug. Thesecompositions can be prepared by mixing the drug with a suitablenon-irritating excipient that is solid at ordinary temperatures butliquid at the rectal temperature and will therefore melt in the rectumto release the drug. Such materials include cocoa butter andpolyethylene glycols.

Compounds of general Formula I may be administered parenterally in asterile medium. The drug, depending on the vehicle and concentrationused, can either be suspended or dissolved in the vehicle.Advantageously, adjuvants such as local anesthetics, preservatives andbuffering agents can be dissolved in the vehicle.

For disorders of the eye or other external tissues, e.g., mouth andskin, the formulations are preferably applied as a topical gel, spray,ointment or cream, or as a suppository, containing the activeingredients in a total amount of, for example, 0.075 to 30% w/w,preferably 0.2 to 20% w/w and most preferably 0.4 to 15% w/w. Whenformulated in an ointment, the active ingredients may be employed witheither paraffinic or a water-miscible ointment base.

Alternatively, the active ingredients may be formulated in a cream withan oil-in-water cream base. If desired, the aqueous phase of the creambase may include, for example at least 30% w/w of a polyhydric alcoholsuch as propylene glycol, butane-1,3-diol, mannitol, sorbitol, glycerol,polyethylene glycol and mixtures thereof. The topical formulation maydesirably include a compound which enhances absorption or penetration ofthe active ingredient through the skin or other affected areas. Examplesof such dermal penetration enhancers include dimethylsulfoxide andrelated analogs. The compounds of this invention can also beadministered by a transdermal device. Preferably topical administrationwill be accomplished using a patch either of the reservoir and porousmembrane type or of a solid matrix variety. In either case, the activeagent is delivered continuously from the reservoir or microcapsulesthrough a membrane into the active agent permeable adhesive, which is incontact with the skin or mucosa of the recipient. If the active agent isabsorbed through the skin, a controlled and predetermined flow of theactive agent is administered to the recipient. In the case ofmicrocapsules, the encapsulating agent may also function as themembrane. The transdermal patch may include the compound in a suitablesolvent system with an adhesive system, such as an acrylic emulsion, anda polyester patch. The oily phase of the emulsions of this invention maybe constituted from known ingredients in a known manner. While the phasemay comprise merely an emulsifier, it may comprise a mixture of at leastone emulsifier with a fat or an oil or with both a fat and an oil.Preferably, a hydrophilic emulsifier is included together with alipophilic emulsifier which acts as a stabilizer. It is also preferredto include both an oil and a fat. Together, the emulsifier(s) with orwithout stabilizer(s) make-up the so-called emulsifying wax, and the waxtogether with the oil and fat make up the so-called emulsifying ointmentbase which forms the oily dispersed phase of the cream formulations.Emulsifiers and emulsion stabilizers suitable for use in the formulationof the present invention include Tween 60, Span 80, cetostearyl alcohol,myristyl alcohol, glyceryl monostearate, and sodium lauryl sulfate,among others. The choice of suitable oils or fats for the formulation isbased on achieving the desired cosmetic properties, since the solubilityof the active compound in most oils likely to be used in pharmaceuticalemulsion formulations is very low. Thus, the cream should preferably bea non-greasy, non-staining and washable product with suitableconsistency to avoid leakage from tubes or other containers. Straight orbranched chain, mono- or dibasic alkyl esters such as di-isoadipate,isocetyl stearate, propylene glycol diester of coconut fatty acids,isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate,2-ethylhexyl palmitate or a blend of branched chain esters may be used.These may be used alone or in combination depending on the propertiesrequired. Alternatively, high melting point lipids such as white softparaffin and/or liquid paraffin or other mineral oils can be used.

Formulations suitable for topical administration to the eye also includeeye drops wherein the active ingredients are dissolved or suspended insuitable carrier, especially an aqueous solvent for the activeingredients. The antiinflammatory active ingredients are preferablypresent in such formulations in a concentration of 0.5 to 20%,advantageously 0.5 to 10% and particularly about 1.5% w/w. Fortherapeutic purposes, the active compounds of this combination inventionare ordinarily combined with one or more adjuvants appropriate to theindicated route of administration. If administered per os, the compoundsmay be admixed with lactose, sucrose, starch powder, cellulose esters ofalkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesiumstearate, magnesium oxide, sodium and calcium salts of phosphoric andsulfuric acids, gelatin, acacia gum, sodium alginate,polyvinylpyrrolidone, and/or polyvinyl alcohol, and then tableted orencapsulated for convenient administration. Such capsules or tablets maycontain a controlled-release formulation as may be provided in adispersion of active compound in hydroxypropylmethyl cellulose.Formulations for parenteral administration may be in the form of aqueousor non-aqueous isotonic sterile injection solutions or suspensions.These solutions and suspensions may be prepared from sterile powders orgranules having one or more of the carriers or diluents mentioned foruse in the formulations for oral administration. The compounds may bedissolved in water, polyethylene glycol, propylene glycol, ethanol, cornoil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodiumchloride, and/or various buffers. Other adjuvants and modes ofadministration are well and widely known in the pharmaceutical art.

Dosage levels of the order of from about 0.1 mg to about 140 mg perkilogram of body weight per day are useful in the treatment of theabove-indicated conditions (about 0.5 mg to about 7 g per patient perday). The amount of active ingredient that may be combined with thecarrier materials to produce a single dosage form will vary dependingupon the host treated and the particular mode of administration. Dosageunit forms will generally contain between from about 1 mg to about 500mg of an active ingredient. The daily dose can be administered in one tofour doses per day. In the case of skin conditions, it may be preferableto apply a topical preparation of compounds of this invention to theaffected area two to four times a day.

It will be understood, however, that the specific dose level for anyparticular patient will depend upon a variety of factors including theactivity of the specific compound employed, the age, body weight,general health, sex, diet, time of administration, route ofadministration, and rate of excretion, drug combination and the severityof the particular disease undergoing therapy.

For administration to non-human animals, the composition may also beadded to the animal feed or drinking water. It may be convenient toformulate the animal feed and drinking water compositions so that theanimal takes in a therapeutically appropriate quantity of thecomposition along with its diet. It may also be convenient to presentthe composition as a premix for addition to the feed or drinking water.Preferred non-human animals include domesticated animals.

The compounds of the present invention may be administered alone or incombination with at least one additional therapeutic agent or therapy,e.g., radiation therapy, to a patient in need of such treatment. Theadditional therapeutic agent or therapy may be administered at the sametime, separately, or sequentially with respect to the administration ofa compound of the invention. Such additional therapeutic agentsincluded, but are not limited to, anti-cancer agents, anti-inflammatoryagents, and the like.

The compounds of the present invention may be prepared by use of knownchemical reactions and procedures. Representative methods forsynthesizing compounds of the invention are presented below. It isunderstood that the nature of the substituents required for the desiredtarget compound often determines the preferred method of synthesis. Allvariable groups of these methods are as described in the genericdescription if they are not specifically defined below.

Methods of Preparation General Procedure

Representative synthetic procedures for the preparation of compounds ofthe invention are outlined below in following schemes. Unless otherwiseindicated, X₁, X₂, X₃, n, R₅, R₆, R₇, R_(C), R₁₁, and Y carry thedefinitions given in connection with Formula I. The definition of R isas set forth above in connection with Formula XVII.

Those having skill in the art will recognize that the starting materialsand reaction conditions may be varied, the sequence of the reactionsaltered, and additional steps employed to produce compounds encompassedby the present invention, as demonstrated by the following examples. Insome cases, protection of certain reactive functionalities may benecessary to achieve some of the above transformations. In general, theneed for such protecting groups as well as the conditions necessary toattach and remove such groups will be apparent to those skilled in theart of organic synthesis.

The disclosures of all articles and references mentioned in thisapplication, including patents, are incorporated herein by reference intheir entirety.

EXAMPLES

The preparation of the compounds of the invention is illustrated furtherby the following examples, which are not to be construed as limiting theinvention in scope or spirit to the specific procedures and compoundsdescribed in them. In all cases, unless otherwise specified, the columnchromatography is performed using a silica gel solid phase.

Example 1

3,6,6-Trimethyl-1,5,6,7-tetrahydro-indol-4-one (Compound 1)

To a solution of anti-pyruvic aldehyde-1-oxime (10 g, 1 eq) and5,5-dimethyl-1,3-cyclohexanedione (16.1 g, 1 eq) in HOAc—H₂O (7:3, 200mL) was added zinc powder (14.95 g, 2 eq) slowly with cooling by a waterbath at room temperature. The mixture then was refluxed overnight,concentrated to dryness, partitioned between brine (300 mL) anddichloromethane (300 mL). The pH was adjusted to ca. 6 with saturatedaqueous NaHCO₃, then the mixture was extracted with dichloromethane(3×200 mL). The organic layers were combined, dried over Na₂SO₄,filtered, concentrated. The crude product was purified by flashchromatography eluting with 5% ethyl acetate in dichloromethane. Thecombined organic fractions were concentrated, triturated in ether-hexane(2:1) for 1 hour, then filtered, washed with hexane to give the puretitle compound (9 g, 45% yield) as a solid. LCMS m/z: (M+H)=178.1.

Example 2

2-Bromo-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-indol-1-yl)-benzonitrile(Compound 2)

The title compound of Example 1 (9.8 g, 55.3 mmol) and2-bromo-4-fluorobenzonitrile (13.27 g, 66.4 mmol) were dissolved inanhydrous dimethylformamide (DMF, 300 mL). To this was added sodiumhydride (95%, 2.79 g, 111 mmol) and the reaction was stirred at 55° C.for 1 hour. The reaction mixture was cooled to room temperature andwater was added. A tan solid precipitated which was filtered, washedwith water and ether and then dried in vacuo (16.5 g, 84%). LCMS m/z:(M+H)=358.1.

Example 3

2-(trans-4-Hydroxy-cyclohexylamino)-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-indol-1-yl)-benzamide(Compound 3)

A “Personal Chemistry” microwave vial was charged with the titlecompound of Example 2[2-Bromo-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-indol-1-yl)-benzonitrile(1.072 g, 3.0 mmol)], trans-4-aminocyclohexanol (1.382 g, 12.0 mmol),palladium (II) acetate (33.7 mg, 5 mol %),1,1′-bis(diphenylphosphino)ferrocene (DPPF) (166.3 mg, 10 mol %), andsodium tert-butoxide (576.7 mg, 6.0 mmol). To this was added toluene (20mL) and the reaction was heated with microwave irradiation to 115° C.for 15 min. After allowing the reaction vessel to cool, a suspensionformed and was filtered and the filtrate evaporated. The residue waspurified by flash chromatography. The intermediate product washydrolyzed by dissolution in 25% dimethylsulfoxide/ethanol, adding 0.5mL of 1 N sodium hydroxide and 0.5 mL of 30% aqueous hydrogen peroxide,followed by stirring at room temperature for 4 hours. After judging thereaction to be complete by TLC, the DMSO/ethanol mixture was dilutedwith water and extracted with ethyl acetate (3×). The combined organicswere washed with brine (2×), dried over Na₂SO₄, and evaporated. Thecompound was purified by column chromatography eluting with EtOAc-MeOHto yield 575 mg (47% yield) of the title compound as a white powder.LCMS m/z: (M+H)=410.3

Example 4

2-(Tetrahydro-pyran-4-ylamino)-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-indol-1-yl)-benzamide(Compound 4)

A “Personal Chemistry” microwave vial was charged with the titlecompound of Example 2 (2.858 g, 8.0 mmol), 4-aminotetrahydropyran (3.236g, 32.0 mmol), palladium (II) acetate (89.8 mg, 5 mol %),1,1′-bis(diphenylphosphino)ferrocene (443.6 mg, 10 mol %), and sodiumtert-butoxide (1.538 g, 16.0 mmol). The reagents were suspended intoluene (40 mL) and were heated with microwave radiation to atemperature of 115° C. for fifteen minutes. After allowing the reactionvessel to cool, the suspension was filtered and the filtrateconcentrated. After purifying the crude intermediate nitrile by flashchromatography, the nitrile was dissolved in 25%dimethylsulfoxide/ethanol, and 2 mL of 1 N sodium hydroxide and 2 mL of30% aqueous hydrogen peroxide were added, followed by stirring at roomtemperature for 16 hours. The DMSO/ethanol mixture was then diluted withwater and extracted with ethyl acetate (3×). The combined organics werewashed with brine (2×), dried over Na₂SO₄, and evaporated. The residuewas purified by column chromatography (EtOAc/MeOH) to yield 1.132 g(36%) of the title compound as an off-white powder. LCMS m/z:(M+H)=396.7.

Example 5

2-(2-Methoxy-ethylamino)-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-indol-1-yl)-benzamide(Compound 5)

A “Personal Chemistry” microwave vial was charged with the titlecompound of Example 2 (107.1 mg, 0.3 mmol), 2-methoxyethylamine (91.3mg, 1.2 mmol), palladium (II) acetate (3.4 mg, 5 mol %),1,1′-bis(diphenylphosphino)ferrocene (16.6 mg, 10 mol %), and sodiumtert-butoxide (57.7 mg, 0.6 mmol). The reagents were suspended intoluene (2 mL) and were heated with microwave radiation to a temperatureof 115° C. for fifteen minutes. After allowing the reaction vessel tocool, the suspension was filtered and the filtrate evaporated. Afterpurifying the crude intermediate nitrile by flash chromatography,hydrolysis was performed by dissolving the residue in 25%dimethylsulfoxide/ethanol, adding 5 drops of 1 N sodium hydroxide and 5drops of 30% aqueous hydrogen peroxide, followed by stirring at roomtemperature for 3 hours. The DMSO/ethanol mixture was then diluted withwater and extracted with CH₂Cl₂ (3×). The combined organics were washedwith brine (2×), dried over Na₂SO₄, and concentrated. The compound waspurified by column chromatography (hexane/EtOAc) to yield the titlecompound (94.4 mg, 85% yield) of an off-white powder. LCMS m/z: (M+H)370.2.

Example 6

2-(3,4,5-Trimethoxy-phenylamino)-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-indol-1-yl)-benzamide(Compound 6)

A “Personal Chemistry” microwave vial was charged with the titlecompound of Example 2 (107.1 mg, 0.3 mmol), 3,4,5-trimethoxyaniline(219.9 mg, 1.2 mmol), palladium (II) acetate (3.4 mg, 5 mol %),1,1′-bis(diphenylphosphino)ferrocene (16.6 mg, 10 mol %), and sodiumtert-butoxide (57.7 mg, 0.6 mmol). The reagents were suspended intoluene (2 mL) and were heated with microwave radiation to a temperatureof 115° C. for fifteen minutes. After allowing the reaction vessel tocool, the suspension was filtered and the filtrate evaporated. Theresidue was purified by flash chromatography, and hydrolysis wasperformed by dissolving the product in 25% dimethylsulfoxide/ethanol,adding 5 drops of 1 N sodium hydroxide and 5 drops of 30% aqueoushydrogen peroxide, followed by stirring at room temperature for 3 hours.The DMSO/ethanol mixture was then diluted with water and extracted intoEtOAc (3×). The combined organics were washed with brine (2×), driedover Na₂SO₄, and concentrated. The compound was purified by columnchromatography (hexane/EtOAc) to yield 28.4 mg (20%) of the titlecompound as a yellow powder. LCMS m/z: (M+H) 478.3

Example 7

2-[(Pyridin-3-ylmethyl)-amino]-4-(3,6,6-trimethyl-4-ox-4,5,6,7-tetrahydro-indol-1-yl)-benzamide(Compound 7)

A “Personal Chemistry” microwave vial was charged with the titlecompound of Example 2 (107.1 mg, 0.3 mmol), 3-(aminomethyl)pyridine(129.8 mg, 1.2 mmol), palladium (II) acetate (3.4 mg, 5 mol %),1,1′-bis(diphenylphosphino)ferrocene (16.6 mg, 10 mol %), and sodiumtert-butoxide (57.7 mg, 0.6 mmol). The reagents were suspended intoluene (2 mL) and were heated with microwave radiation to a temperatureof 125° C. for fifteen minutes. The crude intermediate nitrile waspurified by flash chromatography (hexane/EtOAc) chromatography.Hydrolysis was performed by dissolving the residue in 25% dimethylsulfoxide/ethanol, adding 4 drops of 1 N sodium hydroxide and 4 drops of30% aqueous hydrogen peroxide, and stirring at room temperature for 15minutes. The DMSO/ethanol mixture was then diluted with water andextracted into EtOAc (3×). The combined organics were washed with brine(2×), dried over Na₂SO₄, and concentrated. The compound was purified bycolumn chromatography (hexane/EtOAc) to yield 50 mg (41%) of the titlecompound as a yellow powder. LCMS m/z: (M+H) 403.

Example 8

2-(4-oxo-cyclohexylamino)-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-indol-1-yl)-benzamide(Compound 8)

The title compound of Example 3[2-(4-Hydroxy-cyclohexylamino)-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-indol-1-yl)-benzamide](150 mg, 0.366 mmol) and Dess-Martin periodinane (0.366 mmol) weredissolved in anhydrous CH₂Cl₂ and stirred at room temperature for onehour. The reaction mixture was concentrated and the title compound wasisolated as a white solid (36.2 mg, 24% yield) after purification bycolumn chromatography eluting with EtOAc-MeOH. LCMS m/z: (M+H)=408.3.

Example 9

2-[trans-4-(2-Morpholin-4-yl-ethoxy)-cyclohexylamino]-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-indol-1-yl)-benzamide(Compound 9)

A microwave reaction vial was charged with the title compound of Example3[2-(trans-4-Hydroxy-cyclohexylamino)-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-indazol-1-yl)-benzamide](100 mg, 0.244 mmol), 4-(2-chloroethyl)morpholine hydrochloride (45.4mg, 0.244 mmol), sodium hydride (17.3 mg, 0.732 mmol), and a catalyticamount of potassium iodide. After suspending in DMF, the reactionmixture was heated to 180° C. in the “Personal Chemistry” microwave foreight minutes. The solution was then diluted with water and extractedinto EtOAc (2×). The organic layers were extracted with 2N HCl (2×). Theaqueous extracts basified with aqueous sodium hydroxide, and wereextracted with EtOAc (3×). The combined organics were dried over Na₂SO₄,concentrated, and purified by column chromatography (EtOAc/MeOH) toyield the title compounds as a white solid. LCMS m/z: (M+H) 523.9.

Example 10

3-bromo-4-cyanophenylhydrazine (Compound 10)

In a clean, dry 250-mL round-bottom flask, 2-bromo-4-fluorobenzonitrile(25.34 g) was dissolved in tetrahydrofuran (50 mL) under N₂. To this wasslowly added anhydrous hydrazine (50 mL). The solution color changedfrom yellow to red-orange. The reaction was allowed to stir at roomtemperature for 16 hours. A yellow-white crystalline solid precipitatedfrom the solution. The mixture was then diluted with THF (50 mL) todissolve the solids. The organic layer was then washed with saturatedsodium bicarbonate solution until the pH of the organic layer wasapproximately 8.5. The organic layer was isolated and the solvent wasremoved under reduced pressure to give a white solid. This was place ina fritted glass funnel and washed with 1.5 L of water, followed by ofdiethyl ether (ca. 200 mL). The ether wash was then combined with thewhite solid and dried under reduced pressure. The title compound wasisolated as a fluffy, white or off-white solid (23.43 g, 87.2% yield).LCMS m/z: calculated=212.05; observed=252.98 (M+H+ acetonitrile).

Example 11

2-Bromo-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-indazol-1-yl)-benzonitrile(Compound 11)

In a clean, dry 20 mL microwave reaction vial, the title compound ofExample 10 (2.49 g) was combined with2-acetyl-5,5-dimethyl-1,3-cyclohexanedione (2.14 g). The contents of thevial were dissolved in ethanol-acetic acid (12 mL, 3:1). The vial wassealed and agitated on a vortex. The vial was then placed in themicrowave reactor and heated to 150° C. for 15 min. The vial was thencooled then placed in the refrigerator for 1 hour. The cooled solutionwas then diluted with water (8 mL) and poured onto a fritted glassfunnel. The orange solid was washed with H₂O (100 mL) followed byethanol (25 mL). The solid was then dried under reduced pressure. Thetitle compound was obtained as of a light-orange crystalline solid(3.7463 g, 88.85% yield). LCMS m/z M+H=358.1.

Example 12

2-(Tetrahydro-pyran-4-ylamino)-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-indazol-1-yl)-benzamide(Compound 12)

The title compound of Example 11 (100 mg, 0.28 mmol), Pd(OAc)₂ (3.2 mg,5 mol %), DPPF (15.5 mg, 10 mol %) and NaO^(t)Bu (54 mg, 0.56 mmol) wereadded to a 2 mL microwave vial. Toluene (0.5 mL) and4-aminotetrahydropyran (56 μL, 0.56 mmol) were added and the vial wasevacuated and back-filled with N₂. The reaction mixture was heated at120° C. for 15 min (microwave). The reaction mixture was filtered andthe solids washed with methylene chloride. The product was purifiedusing flash chromatography eluting with hexanes and ethyl acetate.Product was recovered as an off-white solid (88 mg, 83%), LCMS m/z:(M+H)=379.3. Ethanol (0.8 mL), DMSO (0.2 mL), NaOH (5 N, 93 μL, 2 moleq) and H₂O₂ (0.1 mL, 30% solution in H₂O) were added to the pyrazole(88 mg, 0.23 mmol) in a 2 mL microwave vial. The reaction mixture washeated at 100° C. for 10 min. Product was recovered by washing with H₂Oand ethyl acetate. Solvent was removed in vacuo to yield the titlecompound as a yellow solid (88 mg, 100%), LCMS m/z: (M+H)=397.3.

Example 13

2-(Tetrahydrothiopyran-4-ylamino)-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydroindazol-1-yl)benzamide(Compound 13)

Tetrahydro-thiopyran-4-one (10.0 g, 86.0 mmol) and NH₄OAc (60 g, 10 moleeq) were dissolved in 200 mL of MeOH/H₂O (1:1). To this was addedNaCNBH₃ (10.8 g, 172.0 mmol) and the reaction mixture was allowed tostir at room temperature overnight. Methanol was removed under vacuumand the product was extracted from the aqueous layer with ethyl acetate(3×100 mL) and washed with brine. The organic layer was washed with 10%aqueous HCl (150 mL) that was then basified with 10% NaOH solution (topH 11). The basic solution was then washed with ethyl acetate and driedover MgSO₄, to give 4-aminotetrahydrothiopyran which was used withoutfurther purification, LCMS m/z: (M+H)⁺=118.2. Compound 11 (1.4 g, 3.9mmol), Pd(OAc)₂ (44.7 mg, 5 mol %), DPPF (229 mg, 10 mol %) andNaO^(t)Bu (790 mg, 7.8 mmol) were added to a 20 mL microwave vial.Toluene (12 mL) and 4-aminotetrahydrothiopyran (550 mg, 1.2 mol eq) wereadded and the vial was evacuated and back-filled with N₂. The reactionmixture was heated at 130° C. for 20 min (microwave). The reactionmixture was filtered and the solids washed with CH₂Cl₂. The product waspurified using flash chromatography eluting with Hexanes and Ethylacetate. The product,2-(tetrahydro-thiopyran-4-ylamino)-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-indazol-1-yl)-benzonitrile,was recovered as a off-white solid (350 mg), LCMS m/z (M+H)⁺=395.3.

The preceeding product (830 mg, 2.1 mmol) was dissolved in ethanol (12mL) and DMSO (3 mL) to which NaOH (5 N, 841 μL, 2 mol eq) was added. Thereaction mixture was heated at 70° C. overnight. The reaction mixturewas washed with H₂O and EtOAc. The product was purified by flashchromatography eluting with Hexanes and Ethyl acetate. The titlecompound was obtained as an off-white solid (490 mg), LCMS m/z (M+H)⁺413.2

Example 14

2-(1-Oxo-hexahydro-1-Tetrahydrothiopyran-4-ylamino)-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydroindazol-1-yl)benzamide(Compound 14)

2-(Tetrahydrothiopyran-4-ylamino)-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydroindazol-1-yl)benzamidewas dissolved in ethanol to which H₂O₂ (a few drops of 30% solution inH₂O) was added. The reaction mixture was allowed to stir at rt for 30min. Product was isolated via extraction with EtOAc and H₂O. The titlecompound was obtained as an off-white solid (20 mg), LCMS m/z(M+H)⁺=429.2

Example 15

2-(1,1-Dioxo-hexahydro-1-Tetrahydrothiopyran-4-ylamino)-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydroindazol-1-yl)benzamide(Compound 15)

2-(Tetrahydrothiopyran-4-ylamino)-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydroindazol-1-yl)benzamide(25 mg, 0.063 mmol) was dissolved in a mixture of ethanol (1 mL) andDMSO (0.25 mL) to which NaOH (5 N, 25 μL, 2 mol eq) and H₂O₂ (excess,30% solution in H₂O) was added. The reaction mixture was heated at 70°C. overnight. The reaction mixture was washed with H₂O and EtOAc. Theproduct was purified using flash chromatography eluting withdichloromethane and methanol. The title compound was obtained as anoff-white solid (20 mg), LCMS m/z (M+H)⁺=445.2

Example 16

6,6-Dimethyl-3-trifluoromethyl-1,5,6,7-tetrahydro-indazol-4-one(Compound 16)

A mixture of 5,5-dimethyl-1,3-cyclohexandione (7.0 g, 49.9 mmol, 1.0equiv), p-toluenesulfonylhydrazide (9.3 g, 49.9 mmol, 1.0 eq.), andp-toluenesulfonic acid (100 mg, 0.53 mmol, 0.01 eq.) in 300 mL oftoluene was heated at reflux. After 30 minutes the reaction mixture wascooled, and 50 mL of toluene was added to the reaction mixture. Thereaction was returned to heating at reflux. After 1 hour the reactionmixture was cooled to ambient temperature. The solids were collected byfiltration, washed three times with ether, and dried under vacuum toafford 3,3-dimethyl-5-(p-tolylsulfonylhydrazono)-cyclohexanone (14.26 g,93%) as a light yellow solid: LC/MS (m/z) [M+H]⁺=309.1.

To a solution/suspension of3,3-dimethyl-5-(p-tolylsulfonylhydrazono)-cyclohexanone (4.0 g, 12.97mmol, 1.0 eq.) in 72 ml of tetrahydrofuran and 24 mL of triethylaminewas added trifluoroacetic anhydride (1.8 mL, 12.97 mmol, 1.0 eq.). Thedark red reaction mixture was heated at 55° C. After 15 min the reactionmixture was homogeneous. After 2 h the reaction mixture was cooled toambient temperature. Methanol (16 mL) and a 1:1 solution of water-1 Maqueous sodium hydroxide (16 mL) were added. After stirring for 3 h, thereaction mixture was diluted with 50 mL of saturated aqueous ammoniumchloride and extracted with ethyl acetate (3×50 mL). The combinedorganic layers were washed with brine, dried over sodium sulfate,filtered, and concentrated in vacuo. The residue was filtered through aplug of silica gel, eluting with ethyl acetate. The filtrate wasconcentrated in vacuo, and the residue was treated with ether. Thesolids were collected by filtration and washed with ether. The filtratewas concentrated in vacuo, and the resulting residue was treated withether. The solids were collected by filtration, washed with ether, andcombined with the initial solids to provide6,6-dimethyl-3-trifluoromethyl-1,5,6,7-tetrahydro-indazol-4-one (1.24 g,41%) as a reddish orange solid: LC/MS (m/z): [M+H]⁺ 233.1.

Example 17

2-bromo-4-(6,6-dimethyl-4-oxo-3-trifluoromethyl-4,5,6,7-tetrahydro-indazol-1-yl)-benzonitrile(Compound 17)

Sodium hydride (168 mg, 7.02 mmol, 1.0 eq.) was added to a solution of6,6-dimethyl-3-trifluoromethyl-1,5,6,7-tetrahydro-indazol-4-one (1.63 g,7.02 mmol, 1.0 eq.) in 35 mL of anhydrous dimethyl sulfoxide. After 15min 2-bromo-4-fluorobenzonitrile (2.25 g, 11.23 mmol, 1.6 eq.) was addedas a solid. The reaction mixture was heated at 45° C. After 23 h thereaction mixture was cooled to ambient temperature and quenched with 10mL of saturated aqueous ammonium chloride. The mixture was diluted withwater and extracted with ethyl acetate (4×). The combined organic layerswere washed with brine, dried over sodium sulfate, filtered, andconcentrated in vacuo. The residue was purified on a Biotage (SiO₂,hexanes-ethyl acetate) to afford2-bromo-4-(6,6-dimethyl-4-oxo-3-trifluoromethyl-4,5,6,7-tetrahydro-indazol-1-yl)-benzonitrile(1.83 g, 63%) as an off-white powder, LC/MS: (M+H)=412.0.

Example 18

2-(Cyclopent-3-enylamino)-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-indazol-1-yl)benzamide(Compound 18)

1-(2-Bromo-4-cyanophen-4-yl)-3,6,6-trimethyltetrahydroindazal-4-one (2.0g, 5.6 mmol), Pd(OAc)₂ (64 mg, 5 mol %), DPPF (328 mg, 10 mol %) andNaO^(t)Bu (1.13 mg, 11.2 mmol) were added to a 20 mL microwave vial.Toluene (15 mL) and 1-amino-3-cyclopentene (11.2 mmol) were added andthe vial was evacuated and back-filled with N₂. The reaction mixture washeated at 120° C. for 15 minutes. The reaction mixture was filtered andthe solids washed with CH₂Cl₂. The product was purified using flashchromatography eluting with hexanes and ethyl acetate. Product wasobtained as an off-white solid (1.35 g), LCMS m/z (M+H)⁺=361.2.

The preceeding product (2.71 g, 7.5 mmol) was dissolved in ethanol (20mL) and DMSO (5 mL), and NaOH (5 N, 2.51 mL, 2 mol eq) and H₂O₂ (3.0 mL,30% solution in H₂O) were added. The reaction mixture was stirred atroom temperature for 2 hours. The reaction mixture was washed with H₂Oand extracted with EtOAc. The product was purified using flashchromatography eluting with hexanes and ethyl acetate. The titlecompound was obtained as an off-white solid (490 mg), LCMS m/z:(M+H)⁺=379.2

Example 19

4-(6,6-Dimethyl-4-oxo-3-methyl-4,5,6,7-tetrahydro-indazol-1-yl)-2-(3,4,5-trimethoxyanilino)-benzamide(Compound 19)

Sodium tert-butoxide (269 mg, 2.80 mmol, 2.0 equiv) was added to astirred solution/suspension of2-bromo-4-(6,6-dimethyl-4-oxo-3-methyl-4,5,6,7-tetrahydro-indazol-1-yl)-benzonitrile(500 mg, 1.40 mmol, 1.0 eq.), 3,4,5-trimethoxyaniline (513 mg, 2.80mmol, 2.0 eq.), palladium (II) acetate (16 mg, 0.07 mmol, 0.05 eq.), and1,1′-bis(diphenylphosphino)ferrocene (78 mg, 0.14 mmol, 0.10 eq.) in3.75 mL of toluene. The reaction vial was capped, and the reactionmixture was heated 20 minutes at 120° C. under microwave irradiation.The individual reaction mixtures were diluted with ethyl acetate,combined, and partitioned with water. The layers were separated, and theaqueous layer was extracted with ethyl acetate. The combined organiclayers were washed with brine, dried over sodium sulfate, filtered, andconcentrated in vacuo. The residue was purified on a Biotage System(SiO₂, hexanes-ethyl acetate) to afford4-(6,6-dimethyl-4-oxo-3-methyl-4,5,6,7-tetrahydro-indazol-1-yl)-2-(3,4,5-trimethoxyanilino)-benzonitrile(1.59 g, 82%) as a tan solid: LC/MS (m/z): [M+H]⁺ 461.9.

To a mixture of4-(6,6-dimethyl-4-oxo-3-methyl-4,5,6,7-tetrahydro-indazol-1-yl)-2-(3,4,5-trimethoxyanilino)-benzonitrile(1.56 g, 3.39 mmol, 1.0 eq.) in 17 mL of a mixture of 4:1ethanol-dimethyl sulfoxide was added 2 mL of 1 M aqueous sodiumhydroxide and 2 mL of 30% hydrogen peroxide. After 3 hours the reactionmixture was diluted with water and extracted with ethyl acetate (3×).The combined organic layers were washed with brine, dried over sodiumsulfate, filtered, and concentrated in vacuo to afford the titlecompound,4-(6,6-dimethyl-4-oxo-3-methyl-4,5,6,7-tetrahydro-indazol-1-yl)-2-(3,4,5-trimethoxyanilino)-benzamide,(1.61 g, 99%) as a tan solid: LC/MS (m/z): [M+H]⁺ 479.3.

Example 20

Amino-acetic acidtrans-4-[2-carbamoyl-5-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-indol-1-yl)-phenylamino]-cyclohexylester; methanesulfonic acid salt (Compound 20)

2-(trans-4-Hydroxy-cyclohexylamino)-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-indol-1-yl)-benzamide(750.0 mg, 1.832 mmol), N-(tert-butoxycarbonyl)glycine (641.8 mg, 3.664mmol, 2.0 eq.), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (702.4 mg, 3.664 mmol, 2.0 eq.) and a catalytic amount of4-dimethylaminopyridine were dissolved in 20 mL of CH₂Cl₂ and stirred atroom temperature for sixteen hours. The solvent was removed in vacuo,and the residue purified by column chromatography (eluting with EtOAc),yielding 780.5 mg (75.2% yield) of a Boc protected pale yellow foam.

The preceeding product was dissolved in 15 mL of CH₂Cl₂ and cooled to 0°C. in an ice bath. 15 mL of trifluoroacetic acid was then added and thereaction mixture stirred at 0° C. for 5 minutes and 30 minutes at roomtemperature. The trifluoroacetic acid and CH₂Cl₂ were removed in vacuo,and the residue dissolved in water. The aqueous solution was basified byaddition of saturated aqueous sodium bicarbonate. The aqueous suspensionwas extracted with EtOAc (3×), and the combined organics washed withwater and dried over Na₂SO₄. Removal of the solvent in vacuo yielded569.7 mg (66.6% yield through coupling and deprotection) of an off-whitefoam, which by LC/MS showed pure product (m/z: (M+H)=467.3). This freebase was then converted to the mesylate salt by dissolution in CH₂Cl₂,and adding one equivalent dropwise of methanesulfonic acid, followed bystirring at room temperature for 1 hour. Removal of the solvent in vacuoyielded 680.7 mg of the title compound as an off-white powder.

Example 21

Dimethylamino-acetic acidtrans-4-[2-carbamoyl-5-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-indol-1-yl)-phenylamino]-cyclohexylester; methanesulfonic acid salt (Compound 21)

The procedure of Example 20 was used, substituting dimethylamino-aceticacid for N-(tert-butoxycarbonyl)glycine to give the title compound. LCMSm/z: (M+H)=495.2.

Example 22

2-[3-(2-Dimethylamino-ethoxy)-4-methoxy-phenylamino]-4-(6,6-dimethyl-4-oxo-3-trifluoromethyl-4,5,6,7-tetrahydro-indazol-1-yl)-benzamide(Compound 22)

To a solution of 2-methoxy-5-nitro-phenol (10 g),(2-chloro-ethyl)-dimethyl-amine hydrochloride (9.37 g) indimethylformamide (150 mL) was added NaH (2.98 g) slowly under N₂ and atroom temperature. The mixture was then stirred at 140° C. heating withan oil bath for 5 hours. The reaction was concentrated to dryness,dissolved in 2 M HCl (200 mL) and washed with ethyl acetate (2×100 mL).The aqueous layer was basified with K₂CO₃, extracted withdichloromethane (3×200 mL) and ethyl acetate (2×100 mL), dried overNa₂SO₄, filtered, concentrated to give[2-(2-Methoxy-5-nitro-phenoxy)-ethyl]-dimethylamine (9.17 g, 65% yield).LCMS (m/z) M+H: 241.1.

The preceding product (10.53 g) and 10% Pd/C (1 g) were mixed with EtOH(200 mL) and hydrogenated at 50 psi overnight. The reaction mixture wasfiltered through a Celite plug, and the filter cake was washed withMeOH. The filtrate was concentrated to dryness to give3-(2-dimethylamino-ethoxy)-4-methoxy-phenylamine (9.05 g, 98% yield).LCMS (m/z) M+H: 211.2.

2-bromo-4-(6,6-dimethyl-4-oxo-3-trifluoromethyl-4,5,6,7-tetrahydro-indazol-1-yl)-benzonitrile(500 mg, 1 eq), 3-(2-dimethylamino-ethoxy)-4-methoxy-phenylamine (306mg, 1.2 eq), Pd(OAc)₂ (14 mg), DPPF (66 mg), and NaOtBu (214 mg, 2 eq)were mixed in toluene (5 mL) and microwaved at 140° C. for 25 minutes.Then 10 mL of EtOH(4)/H₂O(1) were added, followed by NaOH (700 mg, 2 eq)and H₂O₂ (1 mL). The mixture was microwaved at 100° C. for 15 min, thenconcentrated to dryness, and purified by flash chromatography, elutingwith 20% EtOH in dichloromethane to give the title compound (480 mg, 71%two-step yield). LCMS (m/z): M+H=560.3.

Example 23

4-(6,6-Dimethyl-4-oxo-3-trifluoromethyl-4,5,6,7-tetrahydro-indazol-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide(Compound 23)

4-Aminotetrahydropyran (245 mg, 2.42 mmol, 2.0 eq) and sodiumtert-butoxide (233 mg, 2.42 mmol, 2.0 eq) were added to a stirredsolution/suspension of2-bromo-4-(6,6-dimethyl-4-oxo-3-trifluoromethyl-4,5,6,7-tetrahydro-indazol-1-yl)-benzonitrile(500 mg, 1.21 mmol, 1.0 eq), palladium (II) acetate (14 mg, 0.06 mmol,0.05 eq), and DPPF (67 mg, 0.12 mmol, 0.10 eq) in 3.75 mL of toluene.The reaction vial was capped, and the reaction mixture was heated 20minutes at 120° C. under microwave irradiation. The reaction mixture wasdiluted with water and ethyl acetate and combined. The layers wereseparated, and the aqueous layer was extracted with ethyl acetate (3×).The combined organic layers were washed with brine, dried over sodiumsulfate, filtered, and concentrated in vacuo. The residue was purifiedon a Biotage system (SiO₂, hexanes-ethyl acetate) to afford4-(6,6-dimethyl-4-oxo-3-trifluoromethyl-4,5,6,7-tetrahydro-indazol-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzonitrile(772 mg, 49%) as a tan solid: LC/MS (m/z): [M+H]⁺ 433.7. Further elutionwith ethyl acetate afforded4-(6,6-dimethyl-4-oxo-3-trifluoromethyl-4,5,6,7-tetrahydro-indazol-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide(713 mg, 44%) as a yellow solid: LC/MS (m/z): [M+H]⁺ 451.2.

To a solution/suspension of4-(6,6-dimethyl-4-oxo-3-trifluoromethyl-4,5,6,7-tetrahydro-indazol-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzonitrile(772 mg, 1.79 mmol, 1.0 eq) in 10 mL of 4:1 ethanol-dimethyl sulfoxidewas added 1 mL of 1 M aqueous sodium hydroxide and 1 mL of 30% hydrogenperoxide. After 30 minutes the reaction mixture was diluted with waterand extracted with ethyl acetate (4×). The combined organic layers werewashed with brine, dried over sodium sulfate, filtered, and concentratedin vacuo to afford the title compound,4-(6,6-dimethyl-4-oxo-3-trifluoromethyl-4,5,6,7-tetrahydro-indazol-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide(788 mg, 98%) as a tan solid: LC/MS (m/z): [M+H]⁺ 451.2.

Example 24

3-Difluoromethyl-6,6-dimethyl-1,5,6,7-tetrahydro-indazol-4-one (Compound24)

A mixture of 5,5-Dimethyl-cyclohexane-1,3-dione (10 g),p-toluenesulfonylhydrazide (13.3 g) p-toluesulfonic acid (140 mg) intoluene (450 mL) was refluxed for 0.5 h. Then 100 mL of toluene wasadded and the mixture was refluxed for another 1 h. The mixture wascooled to room temperature, filtered, the solids were washed by ether(3×200 mL), and dried completely to give the hydrazone as a solid (20.4g, 92.7%). LCMS M+H, 309.1 (MW: 308). It was used in the next stepwithout further purification.

The preceeding product (8.86 g) was dissolved in a mixture oftetrahydrofuran (100 mL) and triethylamine (30 mL), placed under N₂, anddifluoroacetic anhydride (5 g) was added slowly while swirling, then themixture was heated to 55° C. overnight. The mixture was cooled to roomtemperature, and MeOH (35.5 mL) was added, followed by 35.5 mL of a 1:1mixture of H₂O and 1 N NaOH. This mixture was stirred at roomtemperature for 3 h. The reaction mixture was diluted with saturatedaqueous NH₄Cl (120 mL), extracted with ethyl acetate (4×150 mL), driedover Na₂SO₄, filtered, concentrated, purified by column chromatographyeluting with a 1:1 mixture of ethyl acetate and hexanes to give3-difluoromethyl-6,6-dimethyl-1,5,6,7-tetrahydro-indazol-4-one (3.12 g,50.6%). LCMS (M+H): 215.1 (MW: 214).

Example 25

2-Bromo-4-(3-difluoromethyl-6,6-dimethyl-4-oxo-4,5,6,7-tetrahydro-indazol-1-yl)-benzonitrile(Compound 25)

NaH (350 mg) was added to a solution of3-difluoromethyl-6,6-dimethyl-1,5,6,7-tetrahydro-indazol-4-one (3.12 g)in DMSO (75 mL) at room temperature. After 20 minutes of stirring,2-bromo-4-fluorobenzonitrile (4.67 g) was added and stirred at 45° C.overnight. The reaction was diluted with saturated aqueous NH₄Cl (100mL), H₂O (100 mL). The mixture was extracted with ethyl acetate (4×150mL), dried over Na₂SO₄, filtered, concentrated, purified by columnchromatography eluting with a 1:2 mixture of ethyl acetate/hexanes. Theconcentrate of desired fractions was made into a slurry in ether,stirred for 2 h, filtered, washed by hexane to give pure solid2-bromo-4-(6,6-dimethyl-4-oxo-3-difluoromethyl-4,5,6,7-tetrahydro-indazol-1-yl)-benzonitrile(2.82 g, 49.2%). LCMS m/z: (M+H)=395.65, (MW: 394).

Example 26

4-(6,6-Dimethyl-4-oxo-3-difluoromethyl-4,5,6,7-tetrahydro-indazol-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide(Compound 26)

The following reaction was conducted at the 300 mg scale and induplicate at the 500 mg scale: 4-Aminotetrahydropyran (154 mg, 1.52mmol, 2.0 eq.) and sodium tert-butoxide (146 mg, 1.52 mmol, 2.0 eq.)were added to a stirred solution/suspension of2-bromo-4-(6,6-dimethyl-4-oxo-3-difluoromethyl-4,5,6,7-tetrahydro-indazol-1-yl)-benzonitrile(300 mg, 0.76 mmol, 1.0 eq.), palladium (II) acetate (8.5 mg, 0.04 mmol,0.05 eq.), and 1,1′-bis(diphenylphosphino)ferrocene (42 mg, 0.08 mmol,0.1 eq.) in toluene (2.25 mL). The reaction vial was capped, and thereaction mixture was heated for 20 min at 120° C. under microwaveirradiation. The reaction mixture was diluted with water and ethylacetate and combined. The layers were separated, and the aqueous layerwas extracted with ethyl acetate (3×). The combined organic layers werewashed with brine, dried over sodium sulfate, filtered, and concentratedin vacuo. The residue was purified on a Biotage system (SiO₂,hexanes-ethyl acetate) to afford4-(6,6-dimethyl-4-oxo-3-difluoromethyl-4,5,6,7-tetrahydro-indazol-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzonitrile(897 mg, 65% yield) as a tan solid: LC/MS (m/z): [M+H]⁺ 415.2. Furtherelution with ethyl acetate afforded the title compound,4-(6,6-dimethyl-4-oxo-3-difluoromethyl-4,5,6,7-tetrahydro-indazol-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide,(131 mg, 9%) as a yellow solid: LC/MS (m/z): [M+H]⁺ 433.3.

To a solution/suspension of4-(6,6-dimethyl-4-oxo-3-difluoromethyl-4,5,6,7-tetrahydro-indazol-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzonitrile(897 mg, 2.16 mmol, 1.0 eq) in 10.8 mL of 4:1 mixture ofethanol-dimethyl sulfoxide was added 1 mL of 1 M aqueous sodiumhydroxide and 1 mL of 30% hydrogen peroxide. After 30 minutes thereaction mixture was diluted with water and extracted with ethylacetate. The combined organic layers were washed with brine, dried oversodium sulfate, filtered, and concentrated in vacuo to afford the titlecompound,4-(6,6-dimethyl-4-oxo-3-difluoromethyl-4,5,6,7-tetrahydro-indazol-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide,(869 mg, 93%) as a tan solid: LC/MS (m/z): [M+H]⁺ 433.3.

Example 27

2-[3-(2-Dimethylamino-ethoxy)-4-methoxy-phenylamino]-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-indazol-1-yl)-benzamide(Compound 27)

2-Bromo-4-(6,6-dimethyl-4-oxo-3-methyl-4,5,6,7-tetrahydro-indazol-1-yl)-benzonitrile(100 mg, 0.28 mmol), Pd(OAc)₂ (3.1 mg, 5 mol %), DPPF (15.5 mg, 10 mol%) and NaO^(t)Bu (52 mg, 0.56 mmol) were added to a microwave vial.Toluene (0.5 mL) and 3-(2-dimethylamino-ethoxy)-4-methoxy-phenylamine(118 mg, 2 mol eq) were added and the vial was evacuated and back-filledwith N₂. The reaction mixture was heated at 130° C. for 30 min(microwave). The reaction mixture was filtered and the solids washedwith CH₂Cl₂. The product nitrile was purified using flash chromatographyeluting with CH₂Cl₂ and methanol. This nitrile (32 mg, 0.66 mmol) wasdissolved in ethanol (0.8 mL) and DMSO (0.2 mL) to which NaOH (5 N, 26μL, 2 eq) and H₂O₂ (excess, 30% solution in H₂O) was added. The reactionmixture was stirred at room temperature for 1 hour. The reaction mixturewas washed with H₂O and extracted with EtOAc. The product was purifiedusing flash chromatography eluting with CH₂Cl₂ and methanol. The titlecompound was obtained as a yellow solid (10 mg, 30%); LC/MS (m/z):M+H=506.5.

Example 28

4-(3-Cyclopropylmethyl-6,6-dimethyl-4-oxo-4,5,6,7-tetrahydro-indazol-1-yl)-benzamide(Compound 28)

5,5-Dimethyl-1,3-cyclohexanedione (1.051 g, 7.5 mmol, 1.5 eq),cyclopropylacetic acid (500.6 mg, 5.0 mmol), and 4-dimethylaminopyridine(916.3 mg, 7.5 mmol, 1.5 eq) were dissolved in 10 mL of CH₂Cl₂, cooledto 0° C. in an ice bath. A solution of N,N′-dicyclohexylcarbodiimide(1.238 g, 16.0 mmol, 1.2 eq) in 5 mL of CH₂Cl₂ was added dropwise overtwo minutes to the cyclohexanedione solution. The reaction mixture wasthen stirred at 0° C. for 10 minutes and at room temperature for 16hours. The reaction mixture was then filtered and the filtrate purifiedby column chromatography (hexane to 30% EtOAc/hexane) to yield 1.022 g(92% yield) 2-(2-Cyclopropyl-acetyl)-5,5-dimethyl-cyclohexane-1,3-dioneas a pale yellow oil.

2-(2-Cyclopropyl-acetyl)-5,5-dimethyl-cyclohexane-1,3-dione (111.1 mg,0.5 mmol) and 4-cyanophenylhydrazine hydrochloride (84.8 mg, 0.5 mmol,1.0 eq) were suspended in 4 mL of 3:1 EtOH:AcOH and microwaved at 100°C. for 10 minutes. The solvent was removed in vacuo and the resultantresidue purified by column chromatography to yield 81.8 mg (51% yield)of4-(3-Cyclopropylmethyl-6,6-dimethyl-4-oxo-4,5,6,7-tetrahydro-indazol-1-yl)-benzonitrileas an off-white powder.

After dissolving the nitrile in 10 mL of 4:1 EtOH-DMSO, approximately0.1 mL of 1 N NaOH (aq.) and 0.1 mL of 30% H₂O₂ (aq.) were added and thesolution stirred for 1.5 hours. The reaction mixture was poured intobrine, extracted with EtOAc (×3), and the combined organics washed withbrine (×2). The organic extracts were dried over Na₂SO₄ and concentratedin vacuo to afford 73.2 mg (43% yield) of4-(3-Cyclopropylmethyl-6,6-dimethyl-4-oxo-4,5,6,7-tetrahydro-indazol-1-yl)-benzamideas an off-white solid. LCMS (m/z): M+H=339.4.

Example 29

2-[2-(2-Dimethylamino-ethoxy)-pyridin-4-ylamino]-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-indazol-1-yl)-benzamide,methansulfonic acid salt (Compound 29)

2-Chloro-4-nitropyridine (5.3 g, 33.43 mmol) andN,N-dimethylethanolamine (8 mL) were sealed in a pressure tube andstirred at 110° C. for 24 hours. The reaction mixture was thenconcentrated and dried under reduced pressure to remove excessN,N-dimethylethanolamine. The resulting yellow residue diluted with 1 NHCl, and a yellow solid, which was identified as2-chloro-4-nitropyridine, was collected by filtration. The acidicaqueous solution was washed with EtOAc (×2), made basic by the additionof 3 N NaOH, and extracted into EtOAc (x 4). The combined organics weredried-over Na₂SO₄ and the solvent removed in vacuo, yielding 3.55 g(50.3% yield) ofN,N-dimethyl-N′-(4-nitro-pyridin-2-yl)-ethane-1,2-diamine as an orangesolid.

This product (3.55 g, 16.807 mmol) was dissolved in 60 mL ethanol. Aboutfive drops of conc. HCl was added, followed by addition of a spatula tipof Pd/C (10% wt). The reaction vessel was purged with N₂ filled with H₂and evacuated three times, and filled with H₂ to a pressure of 60 psi.After shaking at room temperature for three hours, complete reduction ofthe nitro group was verified by LC/MS. The reaction mixture was filteredthrough Celite and the solvent removed in vacuo. The residue was thendissolved in EtOAc, washed with saturated aqueous NaHCO₃, water, andbrine, and dried over Na₂SO₄. After removing the solvent in vacuo, 2.95g (48.7% yield over two steps) of2-(2-dimethylamino-ethoxy)-pyridin-4-ylamine as a waxy red solid wasobtained.

2-Bromo-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-indazol-1-yl)-benzonitrile(358.2 mg, 1.0 mmol), 2-(2-dimethylamino-ethoxy)-pyridin-4-ylamine(362.5 mg, 2.0 mmol, 2.0 eq.), palladium (II) acetate (11.2 mg, 5 mol%), 1,1′-bis(diphenylphosphino)ferrocene (55.4 mg, 10 mol %), and sodiumtert-butixide (192.2 mg, 2.0 mmol, 2.0 eq.) were suspended in 4 mL oftoluene. The reaction mixture was microwaved at 120° C. for 20 minutes.After cooling the reaction mixture, the solvent was removed in vacuo,and the residue diluted with water. The aqueous suspension was extractedwith EtOAc×3 and the combined organics washed with brine, dried overNa₂SO₄, and concentrated under reduced pressure. The intermediatenitrile and the desired amide were collected and combined afterpurifying by column chromatography (EtOAc/MeOH), and were dissolved in20 mL of 4:1 EtOH/DMSO. Five drops of 1 N NaOH and five drops of 30%H₂O₂ were added, and the reaction mixture stirred at room temperaturefor 2 hours. The solution was diluted with water, extracted into EtOAc(×3), and the combined organics washed with brine (×2), dried overNa₂SO₄, and concentrated under reduced pressure. The resultant residuewas purified by column chromatography (EtOAc/MeOH), yielding 347.3 mg(72.9% yield) of a pink foam. This was dissolved in CH₂Cl₂ and treatedwith of one equivalent of methanesulfonic acid, stirring at roomtemperature for 1 hour. The mixture was evaporated under reducedpressure to yield the title compound. LCMS m/z (M+H)=477.3.

Example 30

2-(2,3-Dihydroxy-propylamino)-4-(6,6-dimethyl-4-oxo-3-trifluoromethyl-4,5,6,7-tetrahydro-indazol-1-yl)-benzamide(Compound 30)

A mixture of 2,4-Difluoro-benzonitrile (1.39 g, 10 mmol),3-amino-propane-1,2-diol (0.911 g, 10 mmol), and ethyl-diisopropyl-amine(1.74 mL) in DMSO (10 mL) was microwaved at 200° C. for 7 min. Then thereaction mixture was poured into a saturated NH₄Cl aq. solution (100mL), extracted with EtOAc (3×100 mL), dried over Na₂SO₄, filtered,concentrated. The crude mixture was purified by flash silica gelchromatography (EtOAc-Hexane 1:1) to give2-(2,3-Dihydroxy-propylamino)-4-fluoro-benzonitrile (0.87 g, 41.4%yield). LCMS (m/z): M+H=211.

To a mixture of6,6-Dimethyl-3-trifluoromethyl-1,5,6,7-tetrahydro-indazol-4-one (0.961g, 4.14 mmol, 1 eq) and NaH (99 mg, 4.14 mmol, 1 eq) in dimethylacetamide (20 mL) was added slowly2-(2,3-Dihydroxy-propylamino)-4-fluoro-benzonitrile (0.87 g, 4.14 mmol,1 eq). Then the reaction mixture was stirred at 150° C. overnight,cooled, poured into saturated NH₄Cl aq. solution (100 mL), extracted byEtOAc (3×150 mL), dried over Na₂SO₄, filtered, concentrated. The crudeproduct was purified by flash silica gel chromatography, eluted by EtOActo give2-(2,3-Dihydroxy-propylamino)-4-(6,6-dimethyl-4-oxo-3-trifluoromethyl-4,5,6,7-tetrahydro-indazol-1-yl)-benzonitrile(1.7 g, 97% yield). LCMS (m/z): M+H=423.

2-(2,3-Dihydroxy-propylamino)-4-(6,6-dimethyl-4-oxo-3-trifluoromethyl-4,5,6,7-tetrahydro-indazol-1-yl)-benzonitrile(1.7 g, 4 mmol, 1 eq), NaOH (806 mg, 20 mmol, 5 eq), and H₂O₂ (3 mL)were dissolved in EtOH-water (4:1) (40 mL). The mixture was microwavedat 120° C. for 15 min, then concentrated to dryness, and purified byflash chromatography, eluted by 10% MeOH in EtOAc to give pure2-(2,3-Dihydroxy-propylamino)-4-(6,6-dimethyl-4-oxo-3-trifluoromethyl-4,5,6,7-tetrahydro-indazol-1-yl)-benzamide(0.52 g, 29% yield). LCMS (m/z): M+H=441.

Example 31

4-(6,6-Dimethyl-4-oxo-3-trifluoromethyl-4,5,6,7-tetrahydro-indazol-1-yl)-2-(tetrahydro-thiopyran-4-ylamino)-benzamide(Compound 31)

1-(2-Bromo-4-cyanophen-4-yl)-3-trifluoromethyl-6,6-dimethyltetrahydroindazal-4-one(313 mg, 0.76 mmol), Pd(OAc)₂ (8.7 mg, 5 mol %), DPPF (44.5 mg, 10 mol%) and NaO^(t)Bu (153 mg, 1.52 mmol) were added to a microwave vial.Toluene (1 mL) and 4-aminotetrahydrothiopyran (116 mg, 1.3 mol eq) wereadded and the vial was evacuated and back-filled with N₂. The reactionmixture was heated at 130° C. for 20 min (microwave). The reactionmixture was filtered and the solids washed with CH₂Cl₂. The product waspurified using flash chromatography eluting with hexanes and EtOAc.Product was recovered as a off-white solid (23 mg, 7%), LCMS(M+H)⁺=449.4

This pyrazole (23 mg, 0.05 mmol) was dissolved in ethanol (0.8 mL) andDMSO (0.2 mL) to which NaOH (5 N, 21 μL, 2 mol eq) was added and thereaction mixture was heated at 70° C. for 12 hours. The reaction mixturewas washed with water and EtOAc. The product was purified using flashchromatography eluting with hexanes and EtOAc. The title compound wasobtained as an off-white solid (16 mg, 67%); LC/MS (m/z): M+H=467.2.

Example 32

4-(3-Difluoromethyl-6,6-dimethyl-4-oxo-4,5,6,7-tetrahydro-indazol-1-yl)-2-(tetrahydro-thiopyran-4-ylamino)-benzamide(Compound 32)

2-Bromo-4-(3-difluoromethyl-6,6-dimethyl-4-oxo-4,5,6,7-tetrahydro-indazol-1-yl)-benzamide(300 mg, 0.76 mmol), Pd(OAc)₂ (8.7 mg, 5 mol %), DPPF (44.5 mg, 10 mol%) and NaO^(t)Bu (153 mg, 1.52 mmol) were added to a microwave vial.Toluene (1 mL) and 4-aminotetrahydrothiopyran (116 mg, 1.3 mol eq) wereadded and the vial was evacuated and back-filled with N₂. The reactionmixture was heated at 120° C. for 15 min (microwave). The reactionmixture was filtered and the solids washed with CH₂Cl₂. The product waspurified using flash chromatography eluting with hexanes and EtOAc.Product was recovered as an off-white solid (70 mg, 21%).

The preceding product pyrazole (70 mg, 0.16 mmol) was dissolved inethanol (0.8 mL) and DMSO (0.2 mL) to which NaOH (5 N, 65 mL, 2 eq) wasadded and the reaction mixture was heated at 70° C. for 12 hours. Thereaction mixture was washed with H₂O and EtOAc. The product was purifiedusing flash chromatography eluting with hexanes and EtOAc. The titlecompound was obtained as an off-white solid (40 mg, 56% yield), LC/MS(m/z): M+H=449.2.

Example 33

2-[(Tetrahydro-furan-2-ylmethyl)-amino]-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-indazol-1-yl)-benzamide(Compound 33)

2-Bromo-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-indazol-1-yl)-benzonitrile(1.0 mmol, 358 mg), palladium acetate (0.13 mmol, 30 mg),1,1′-bis(diphenylphosphino)ferrocene (0.1 mmol, 56 mg), sodiumt-butoxide (2 mmol, 192 mg), toluene (2 mL), and2-(aminomethyl)tetrahydrofuran (3 mmol, 0.31 mL) were combined in amicrowave tube, stirred briefly, and heated in a Personal Chemistrymicrowave set at high absorbance to 110° C. for 900 seconds. Aftercooling, the reaction mixture was taken up in ethyl acetate (200 mL) andwashed with water (50 mL). The organic phase was dried over magnesiumsulfate, filtered, and concentrated. The residue was subjected tochromatography, affording the desired nitrile intermediate as a tansolid (305 mg, 81% yield).

DMSO (6 drops) and ethanol (4 mL) were added to the above nitrile (0.79mmol, 300 mg). The flask was lowered into a 50° C. oil bath and KOH (5.8mmol, 325 mg) was added, followed by 30% hydrogen peroxide (ca. 10 mmol,1 mL). After 45 minutes, the reaction was taken up in ethyl acetate (100mL) and washed with water (50 mL). The organic layer was dried overmagnesium sulfate, filtered, and concentrated. Chromatography of theresidue afforded the title compound as a white solid (313 mg, 100%yield). LCMS (m/z): M+H=397.3.

Example 34

2-[3-(2-Oxo-pyrrolidin-1-yl)-propylamino]-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-indazol-1-yl)-benzamide(Compound 34)

2-Bromo-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-indazol-1-yl)-benzonitrile(1.0 mmol, 358 mg), palladium acetate (0.13 mmol, 30 mg),1,1′bis(diphenylphosphino)ferrocene (0.1 mmol, 56 mg), sodium t-butoxide(2 mmol, 192 mg), toluene (2 mL), and N-(3-aminopropyl)-2-pyrrolidinone(2 mmol, 0.28 mL) were combined in a 2-5 mL microwave tube, stirredbriefly, and heated in a Personal Chemistry microwave set at highabsorbance to 110° C. for 900 seconds. After cooling, the reactionmixture was taken up in ethyl acetate (200 mL) and washed with water (25mL). The aqueous layer was extracted with additional ethyl acetate (200mL), and the combined organic phase was dried over magnesium sulfate,filtered, and concentrated. The residue was subjected to chromatography,affording the desired nitrile as a tan solid (258 mg, 61%).

DMSO (0.1 mL) and ethanol (4 mL) were added to the above nitrile (0.60mmol, 250 mg). The flask was lowered into a 50° C. oil bath and KOH (4.5mmol, 255 mg) was added, followed by 30% hydrogen peroxide (ca 10 mmol,1 mL). After 30 minutes, the reaction was taken up in ethyl acetate (100mL) and washed with water (50 mL). The aqueous layer was extracted withadditional ethyl acetate (100 mL). The combined organic layer was driedover magnesium sulfate, filtered, and concentrated. Chromatography ofthe residue afforded the title benzamide as a white solid (187 mg, 71%).LCMS (m/z): M+H=438.2.

Example 35

2-(2,2,2-Trifluoro-ethylamino)-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-indazol-1-yl)-benzamide(Compound 35)

2-Bromo-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-indazol-1-yl)-benzonitrile(2.0 mmol, 714 mg), palladium acetate (0.13 mmol, 60 mg),1,1′-bis(diphenylphosphino)ferrocene (0.2 mmol, 112 mg), sodiumt-butoxide (4 mmol, 384 mg), toluene (4 mL), and2,2,2-trifluoroethylamine (8 mmol, 0.63 mL) were combined in a 2-5 mLmicrowave tube, stirred briefly, and heated in a Personal Chemistrymicrowave set at high absorbance to 110° C. for 900 seconds. Aftercooling, the reaction mixture was taken up in ethyl acetate (200 mL) andwashed with water (25 mL). The organic phase was dried over magnesiumsulfate, filtered, and concentrated. The residue was subjected tochromatography, affording a mixture of the anticipated2-(2,2,2-trifluoro-ethylamino)-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-indazol-1-yl)-benzonitrile(346 mg, 50%) as a tan solid, and the desired ultimate product,2-(2,2,2-trifluoro-ethylamino)-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-indazol-1-yl)-benzamide,as a tan solid (77 mg, 10%). LCMS (m/z): M+H=395.1.

Example 36

The following compounds are prepared essentially according to theprocedures set forth in Schemes 1-4 above and described in the aboveexamples.

Compound No. Structure Name 36

2-(allylamino)-4-(3-methyl-4-oxo- 4,5,6,7-tetrahydroindol-1-yl)benzamide; M + H = 324.1 37

2-(cyclopropylamino)-4-(3-methyl- 4-oxo-4,5,6,7-tetrahydroindol-1-yl)benzamide; M + H = 324.1 38

2-(2-methoxyethylamino)-4-(3- methyl-4-oxo-4,5,6,7-tetrahydroindol-1-yl)benzamide; M + H = 342.1 39

4-(3-methyl-4-oxo-4,5,6,7- tetrahydroindol-1-yl)benzamide; M + H = 269.140

4-(3,6,6-trimethyl-4-oxo-4,5,6,7- tetrahydroindol-1-yl)benzamide; M + H= 297.1 41

4-(3-methyl-4-oxo-4,5,6,7- tetrahydroindol-1-yl)-2-(phenylamino)benzamide; M + H = 360.1 42

2-(trans-4- hydroxycyclohexylamino)-4-(3- methyl-4-oxo-4,5,6,7-tetrahydroindol-1-yl)benzamide; M + H = 382.2 43

4-(3-methyl-4-oxo-4,5,6,7- tetrahydroindol-1-yl)-2-(3,4,5-trimethoxyphenylamino)benzamide; M + H = 450.2 44

2-(2-(dimethylamino)ethylamino)-4- (3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydroindol-1-yl)benzamide; M + H = 383.2 45

2-(2-(dimethylamino)ethylamino)-4- (3-methyl-4-oxo-4,5,6,7-tetrahydroindol-1-yl)benzamide; M + H = 355.2 46

2-(pyridin-4-ylmethylamino)-4- (3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydroindol-1-yl)benzamide; M + H = 403.2 47

4-(3-methyl-4-oxo-4,5,6,7- tetrahydroindol-1-yl)-2-(pyridin-3-ylmethylamino)benzamide; M + H = 375.1 48

tert-butyl 4-(2-carbamoyl-5- (3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydroindol-1- yl)phenylamino)piperidine-1- carboxylate; M + H =495.2 49

2-amino-4-(3,6,6-trimethyl-4-oxo- 4,5,6,7-tetrahydroindol-1-yl)benzamide; M + H = 312.1 50

2-(allylamino)-4-(3,6,6-trimethyl- 4-oxo-4,5,6,7-tetrahydroindol-1-yl)benzamide; M + H = 352.2 51

2-(1-methylpiperidin-4-ylamino)-4- (3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydroindol-1-yl)benzamide; M + H = 409.2 52

2-(piperidin-4-ylamino)-4-(3,6,6- trimethyl-4-oxo-4,5,6,7-tetrahydroindol-1-yl)benzamide; M + H = 395.2 53

3-butoxy-4-(3,6,6-trimethyl-4-oxo- 4,5,6,7-tetrahydroindol-1-yl)benzamide; M + H = 369.2 54

2-(2,3-dihydro-1H-inden-1- ylamino)-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydroindol-1- yl)benzamide; M + H = 428.2 55

1-(2-carbamoyl-5-(3,6,6-trimethyl- 4-oxo-4,5,6,7-tetrahydroindol-1-yl)phenyl)urea M + H = 355.1

Example 37

5,5-dimethyl-2-(2-oxopropyl)cyclohexane-1,3-dione (Compound 56)

An oven dried flask was charged with sodium hydride (3.61 g, 142.7 mmol)to which 200 mL of anhydrous DMF was added. The flask was cooled in anice bath before adding 5,5-dimethyl-1,3-cyclohexanedione (20.0 g, 142.7mmol) and chloroacetone (11.36 mL, 142.7 mmol) in 100 mL DMF in acontrolled manner. The reaction was allowed to warm to RT and stirredfor 3 h. Saturated NH₄Cl was added and the mixture was washed severaltimes with EtOAc. The combined organic layer was dried over MgSO₄,filtered, the solvent removed in vacuo (below 40° C.). LCMS m/zM+H=197.1.

Example 38

2,6,6-trimethyl-6,7-dihydro-1H-indol-4(5H)-one (Compound 57)

The crude tri-ketone from Example 37 was dissolved in 300 mL of aceticacid to which ammonium acetate (55 g, 0.714 mmol) was added. Thereaction mixture was heated at 65° C. until all starting material haddisappeared (2-3 h), cooled to RT, added to H₂O, and washed with EtOAc.The organic layer was washed with saturated NaHCO₃ (×3), brine (×1) anddried over MgSO₄. Solvent was removed in vacuo and the oily residue waspassed through a plug of silica. The appropriate fractions werecollected and solvent was removed. The resulting solid was washed withEtOAc and hexanes (if too much hexanes is added the material crashingback out of solution after the addition of EtOAc will be gummy. Toremedy this simply add a little EtOAc). The solid was filtered andwashed with hexanes. More solid can be recovered by removing the solventand repeating this procedure. LCMS m/z M+H=178.1. Approximately 5 g of atan solid was collected and identified as2,6,6-trimethyltetrahydroindol-4-one.

Example 39

2-bromo-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl)benzonitrile(Compound 58)

Pyrrole (2,6,6-trimethyltetrahydroindol-4-one) (1.5 g, 8.5 mmol) and2-bromo-4-fluorobenzonitrile (1.69 g, 8.5 mmol) were dissolved inanhydrous DMF (50 mL). To this NaH (95%, 408 mg, 17.0 mmol) was addedand stirred at 50° C. for 1 h. The reaction mixture was cooled to RT andH₂O was added. Product crashed out of solution and was filtered anddried under vacuo (2.4 g, 79%). (100% clean by LCMS, product M+H=357).

Example 40

3-fluoro-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl)benzonitrile(Compound 59)

Pyrrole (2,6,6-trimethyltetrahydroindol-4-one) (1.0 g, 5.6 mmol) and3,4-difluorobenzonitrile (785 mg, 5.6 mmol) were dissolved in anhydrousDMF (20 mL). To this NaH (95%, 270 mg, 11.2 mmol) was added and stirredat 50° C. for 30 min. The reaction mixture was cooled to RT and washedwith H₂O and EtOAc. The organic layer was dried over MgSO₄. Columnchromatography on silica eluting with EtOAc-hexanes (1:1) gave theproduct as a yellow solid (100% clean by LCMS, product M+H=397.1).

Example 41

3-butoxy-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl)benzamide(Compound 60)

3-Fluoro-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-indol-1-yl)-benzonitrile(148 mg, 0.5 mmol) and 1-butanol (185.3 mg, 2.5 mmol) were dissolved inanhydrous DMF (1.5 mL). To this solution was added NaH (24.0 mg, 1mmol). After purging the reaction vessel (Personal Chemistry MicrowaveVial) with nitrogen, the reaction vessel was sealed and heated to 100°C. for 300 seconds in an Emyrs Optimizer Microwave. After cooling, thereaction mixture was diluted with H₂O and extracted into EtOAc (×2). Thecombined organics were washed with brine (×2), dried over Na₂SO₄, andconcentrated to dryness. The yellow residue(3-Butoxy-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-indol-1-yl)-benzonitrile)was then dissolved in EtOH (3 mL) and treated with 1 mL of 1 N NaOH (aq)and a catalytic amount of H₂O₂. Quantitative conversion of the nitrileto the amide occurred after heating this solution at 65° C. for 3 hours.Column chromatography on silica eluting with EtOAc gave the product as awhite solid (119.9 mg, 65%). (100% clean by LC/MS, product M+H=369.2).

Example 42

2-(phenylamino)-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl)benzamide(Compound 61)

2-Bromo-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-indol-1-yl)-benzonitrile(107.2 mg, 0.3 mmol), aniline (111.8 mg, 1.2 mmol), Pd(OAc)₂ (10.1 mmol,5 mol %), DPPF (16.6 mg, 10 mol %), and NaOtBu (57.7 mg, 0.6 mmol) wereplaced in a Personal Chemistry Microwave Vial. The reagents weresuspended in 2.5 mL of anhydrous toluene and the vessel purged withnitrogen. The reaction vessel was sealed and heated to 110° C. for 480seconds. Upon cooling, the reaction mixture was filtered through SiO₂(eluted with 2:1 EtOAc/hexanes) and the eluent concentrated in vacuo.The residue was then dissolved in 2 mL EtOH and treated with 0.6 mL of 1N NaOH and a catalytic amount of H₂O₂. After stirring this solution at50° C. for 2 hours, the mixture of nitrile and amide was purified bycolumn chromatography (silica, EtOAc/hexanes). The product2-(phenylamino)-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydroindol-1-yl)benzamidewas isolated as a yellow powder (55.6 mg, 47%). (100% clean by LC/MS,product M+H=388.1). The corresponding nitrile was also isolated (46.9mg, 42%). (100% clean by LC/MS).

Example 43

(Z)-3-butoxy-N′-hydroxy-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl)benzimidamide(Compound 62)

Treatment of3-Butoxy-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-indol-1-yl)-benzonitrilewith hydroxylamine hydrochloride affords the title compound, LCMS m/zM+H=384.2.

Example 44

The following compounds are prepared essentially according to theprocedures forth in Scheme 7-9 and described in the preceding examples.

Compound No. Structure Name 63

2-Benzylamino-4-(2,6,6-trimethyl-4- oxo-4,5,6,7-tetrahydro-indol-1-yl)-benzamide; M + H = 402.2 64

3-Prop-2-ynyloxy-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-indol-1-yl)- benzamide; M + H = 351.1 65

2-Ethynyl-4-(2,6,6-trimethyl-4-oxo- 4,5,6,7-tetrahydro-indol-1-yl)-benzamide; M + H = 321.1 66

2-(4-Methoxy-phenylamino)-4-(2,6,6- trimethyl-4-oxo-4,5,6,7-tetrahydro-indol-1-yl)-benzamide; M + H = 418.2 67

2-Cyclohexylamino-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-indol-1-yl)- benzamide; M + H = 394.1 68

2-(butylamino)-4-(2,6,6-trimethyl-4- oxo-4,5,6,7-tetrahydroindol-1-yl)benzamide; M + H = 368.2 69

4-Methyl-3-(2,6,6-trimethyl-4-oxo- 4,5,6,7-tetrahydro-indol-1-yl)-benzamide M + H = 311.1

Example 45

The following compounds are prepared essentially according to theprocedures forth in Scheme 1-9 and described in the preceding examples.

Compound No. M + H Name 70 379.1 3-(3-thienyl)-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl)benzamide 71 311.12-methyl-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl)benzamide 72 412.12-[(3-ethynylphenyl)amino]-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol- 1-yl)benzamide 73 422.12-[(4-chlorophenyl)amino]-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol- 1-yl)benzamide 74 360.12-anilino-4-(2-methyl-4-oxo-4,5,6,7- tetrahydro-1H-indol-1-yl)benzamide75 389.1 3-anilino-5-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl)pyridine-2- carboxamide 76 478.22-[(3,4,5-trimethoxyphenyl)amino]-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol- 1-yl)benzamide 77 374.12-pyridin-4-yl-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl)benzamide 78 412.2N-[2-(aminocarbonyl)-5-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1- yl)phenyl]-L-valine 79 382.22-morpholin-4-yl-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl)benzamide 80 363.12-(1H-imidazol-1-yl)-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1- yl)benzamide 81 513.24-(3-chloro-2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl)-2-[(3,4,5- trimethoxyphenyl)amino]benzamide 82404.1 2-[(4-hydroxyphenyl)amino]-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol- 1-yl)benzamide 83 406.22-[(1-ethyl-1H-pyrazol-5-yl)amino]-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol- 1-yl)benzamide 84 393.12-[(5-methylisoxazol-3-yl)amino]-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol- 1-yl)benzamide 85 403.12-{[4-(aminocarbonyl)phenyl]amino}-4-(2-methyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1- yl)benzamide 86 436.14-(4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl)-2-[(3,4,5-trimethoxyphenyl)amino]benzamide 87 419.22-[(6-methoxypyridin-3-yl)amino]-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol- 1-yl)benzamide 88 310.12-(allylamino)-4-(4-oxo-4,5,6,7-tetrahydro- 1H-indol-1-yl)benzamide 89283.1 4-(2,3-dimethyl-4-oxo-4,5,6,7-tetrahydro-1H- indol-1-yl)benzamide90 361 3-bromo-4-(2,3-dimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl)benzamide 91 338.12-(allylamino)-4-(2,3-dimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl)benzamide 92 356.14-(2,3-dimethyl-4-oxo-4,5,6,7-tetrahydro-1H- indol-1-yl)-2-[(2-methoxyethyl)amino]benzamide 93 519.22-({3-[3-(dimethylamino)propoxy]-4-methoxyphenyl}amino)-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1- yl)benzamide 94 397.22-(morpholin-4-ylamino)-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1- yl)benzamide 95 371.22-[(2-methoxyethyl)amino]-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H- indazol-1-yl)benzamide 96 425.22-[(2-morpholin-4-ylethyl)amino]-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol- 1-yl)benzamide 97 389.12-(pyridin-4-ylamino)-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1- yl)benzamide 98 354.12-(acetylamino)-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl)benzamide 99 395.22-(4-methylpiperazin-1-yl)-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol- 1-yl)benzamide 100 367.22-[(cyclopropylmethyl)amino]-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H- indazol-1-yl)benzamide 101 384.12-[(methoxyacetyl)amino]-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1- yl)benzamide 102 326.12-ethyl-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indazol-1-yl)benzamide 103 386.12-(butylthio)-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indazol-1-yl)benzamide 104 505.22-({3-[2-(dimethylamino)ethoxy]-4-methoxyphenyl}amino)-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1- yl)benzamide 105 406.12-(pyridin-4-ylthio)-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1- yl)benzamide 106 417.22-{[(1R)-1-phenylethyl]amino}-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H- indazol-1-yl)benzamide 107 533.14-[6,6-dimethyl-4-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]-2-[(3,4,5-trimethoxyphenyl)amino]benzamide 108 476.22-({2-[2-(dimethylamino)ethoxy]pyridin-4-yl}amino)-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl)benzamide 109 480.22-{[1-(N,N-dimethylglycyl)piperidin-4-yl]amino}-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl)benzamide 110 359.14-(6,6-dimethyl-4-oxo-3-phenyl-4,5,6,7-tetrahydro-1H-indol-1-yl)benzamide 111 455.22-[(2-{[2-(aminocarbonyl)-5-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl)phenyl]amino}ethyl)amino]-2-oxoethyl acetate 112 413.22-{[2-(glycoloylamino)ethyl]amino}-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol- 1-yl)benzamide 113 419.12-{[2-(methylsulfonyl)ethyl]amino}-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H- indazol-1-yl)benzamide 114 419.22-[(4-methoxyphenyl)amino]-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H- indazol-1-yl)benzamide 115 406.12-[(6-oxo-1,6-dihydropyridin-3-yl)amino]-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro- 1H-indazol-1-yl)benzamide 116415.2 2-(cyclopent-3-en-1-ylamino)-4-[3-(difluoromethyl)-6,6-dimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indazol-1-yl]benzamide 117 367.22-(cyclobutylamino)-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indazol-1- yl)benzamide 118 455.22-[trans-4-(2-Hydroxy-ethoxy)-cyclohexylamino]-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-indazol-1-yl)-benzamide 119 411.22-(trans-4-Hydroxy-cyclohexylamino)-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro- indazol-1-yl)-benzamide 120415.2 2-(2-Methoxy-1-methoxymethyl-ethylamino)-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro- indazol-1-yl)-benzamide; 121415.2 2-{[3-hydroxy-1-(2- hydroxyethyl)propyl]amino}-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H- indazol-1-yl)benzamide 122 469.24-[6,6-dimethyl-4-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]-2-{[2- methoxy-1-(methoxymethyl)ethyl]amino}benzamide 123 451.12-{[3-(methylsulfinyl)phenyl]amino}-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro- 1H-indazol-1-yl)benzamide 124528.1 4-[6,6-dimethyl-4-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]-2-{[1- (methylsulfonyl)piperidin-4-yl]amino}benzamide 125 465.2 4-(6,6-Dimethyl-4-oxo-3-trifluoromethyl-4,5,6,7-tetrahydro-indazol-1-yl)-2-(trans-4-hydroxy-cyclohexylamino)-benzamide 126 509.24-(6,6-Dimethyl-4-oxo-3-trifluoromethyl-4,5,6,7-tetrahydro-indazol-1-yl)-2-[trans-4-(2-hydroxy-ethoxy)-cyclohexylamino]- benzamide 127 537.32-{[1-(3-morpholin-4-ylpropanoyl)piperidin-4-yl]amino}-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indazol-1-yl)benzamide 128 508.22-[trans-4-(2-Amino-ethoxy)- cyclohexylamino]-4-(6,6-dimethyl-4-oxo-3-trifluoromethyl-4,5,6,7-tetrahydro-indazol- 1-yl)-benzamide 129 453.22-[(1-glycylpiperidin-4-yl)amino]-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H- indazol-1-yl)benzamide 130 454.22-[trans-4-(2-Amino-ethoxy)- cyclohexylamino]-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-indazol-1-yl)-benzamide 131 446.12-{[1-(methylsulfonyl)azetidin-3-yl]amino}-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro- 1H-indazol-1-yl)benzamide132 433.1 2-{[3-(methylsulfonyl)propyl]amino}-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro- 1H-indazol-1-yl)benzamide 133488.1 4-[6,6-dimethyl-4-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]-2-({2-[(methylsulfonyl)amino]ethyl}amino)benzamide 134 338.14-(3-but-3-en-1-yl-6,6-dimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indazol-1-yl)benzamide 135 460.12-{[(3S)-1-(methylsulfonyl)pyrrolidin-3-yl]amino}-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indazol-1-yl)benzamide 136 502.12-({2-[(dimethylamino)sulfonyl]ethyl}amino)-4-[6,6-dimethyl-4-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]benzamide 137 327.14-[3-(2-Amino-ethyl)-6,6-dimethyl-4-oxo-4,5,6,7-tetrahydro-indazol-1-yl]-benzamide

Example 46

The following compounds have been prepared essentially according to theprocedures set forth in Schemes 1-9 above and described in the aboveexamples.

Com- pound M + No. H Name 138 285.14-(6,6-dimethyl-4-oxo-4,5,6,7-tetrahydro-1H- indazol-1-yl)benzoic acid;139 284.1 4-(6,6-dimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indazol-1-yl)benzamide; 140 297.14-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H- indol-1-yl)benzamide;141 313.1 4-[(4Z)-4-(methoxyimino)-6,6-dimethyl-4,5,6,7-tetrahydro-1H-indazol-1-yl]benzamide; 142 299.14-[(4Z)-4-(hydroxyimino)-6,6-dimethyl-4,5,6,7-tetrahydro-1H-indazol-1-yl]benzamide; 143 311.14-methyl-3-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl)benzamide; 144 297.13-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H- indol-1-yl)benzamide;145 332.1 2-chloro-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl)benzoic acid; 146 327.14-[(4Z)-4-(ethoxyimino)-6,6-dimethyl-4,5,6,7-tetrahydro-1H-indazol-1-yl]benzamide; 147 375.14-[(4Z)-6,6-dimethyl-4-(phenoxyimino)-4,5,6,7-tetrahydro-1H-indazol-1-yl]benzamide; 148 355.24-[(4Z)-4-(isobutoxyimino)-6,6-dimethyl-4,5,6,7-tetrahydro-1H-indazol-1-yl]benzamide; 149 339.14-{(4Z)-4-[(allyloxy)imino]-6,6-dimethyl-4,5,6,7-tetrahydro-1H-indazol-1-yl}benzamide; 150 383.24-{(4Z)-6,6-dimethyl-4-[(tetrahydro-2H-pyran-2-yloxy)imino]-4,5,6,7-tetrahydro-1H-indazol-1- yl}benzamide; 151 389.14-{(4Z)-4-[(benzyloxy)imino]-6,6-dimethyl-4,5,6,7-tetrahydro-1H-indazol-1-yl}benzamide; 152 312.14-[(4E)-4-(hydroxyimino)-2,6,6-trimethyl-4,5,6,7-tetrahydro-1H-indol-1-yl]benzamide; 153 326.14-[(4E)-4-(methoxyimino)-2,6,6-trimethyl-4,5,6,7-tetrahydro-1H-indol-1-yl]benzamide; 154 352.14-{(4E)-4-[(allyloxy)imino]-2,6,6-trimethyl-4,5,6,7-tetrahydro-1H-indol-1-yl}benzamide; 155 368.24-[(4E)-4-(isobutoxyimino)-2,6,6-trimethyl-4,5,6,7-tetrahydro-1H-indol-1-yl]benzamide; 156 402.24-{(4E)-4-[(benzyloxy)imino]-2,6,6-trimethyl-4,5,6,7-tetrahydro-1H-indol-1-yl}benzamide; 157 340.13-[(4Z)-4-(methoxyimino)-2,6,6-trimethyl-4,5,6,7-tetrahydro-1H-indol-1-yl]-4- methylbenzamide; 158 326.13-[(4Z)-4-(hydroxyimino)-2,6,6-trimethyl-4,5,6,7-tetrahydro-1H-indol-1-yl]-4- methylbenzamide; 159 377.14-[6-(1,3-benzodioxol-5-yl)-4-oxo-4,5,6,7-tetrahydro-1H-indazol-1-yl]benzoic acid; 160 376.14-[6-(1,3-benzodioxol-5-yl)-4-oxo-4,5,6,7-tetrahydro-1H-indazol-1-yl]benzamide; 161 391.14-[(4Z)-6-(1,3-benzodioxol-5-yl)-4-(hydroxyimino)-4,5,6,7-tetrahydro-1H-indazol-1- yl]benzamide; 162 365.12-(trifluoromethyl)-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl)benzamide; 163 327.12-methoxy-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl)benzamide; 164 369.22-butoxy-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl)benzamide; 165 368.22-(butylamino)-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl)benzamide; 166 385.23-(2-ethoxyethoxy)-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl)benzamide; 167 371.13-(2-methoxyethoxy)-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl)benzamide; 168 341.12-ethoxy-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl)benzamide; 169 357.12-(2-hydroxyethoxy)-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl)benzamide; 170 370.22-[(2-methoxyethyl)amino]-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl)benzamide; 171 385.22-(2-ethoxyethoxy)-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl)benzamide; 172 255.14-(4-oxo-4,5,6,7-tetrahydro-1H-indol-1- yl)benzamide; 173 384.23-[2-(dimethylamino)ethoxy]-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1- yl)benzamide; 174 397.23-(tetrahydrofuran-3-ylmethoxy)-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1- yl)benzamide; 175 407.13-(4-fluorophenoxy)-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl)benzamide; 176 383.22-{[2-(dimethylamino)ethyl]amino}-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1- yl)benzamide; 177 388.12-anilino-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl)benzamide; 178 315.13-fluoro-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl)benzamide; 179 359.14-(6,6-dimethyl-4-oxo-2-phenyl-4,5,6,7-tetrahydro-1H-indol-1-yl)benzamide; 180 331.12-chloro-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl)benzamide; 181 402.22-(benzylamino)-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl)benzamide; 182 3752-bromo-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl)benzamide; 183 357.13-(2-hydroxyethoxy)-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl)benzamide; 184 312.12-amino-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl)benzamide; 185 385.13-(tert-butylthio)-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl)benzamide; 186 405.13-(phenylthio)-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl)benzamide; 187 385.13-(butylthio)-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl)benzamide; 188 340.12-(dimethylamino)-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl)benzamide; 189 327.13-methoxy-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl)benzamide; 190 341.13-ethoxy-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl)benzamide; 191 355.13-propoxy-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl)benzamide; 192 403.13-(benzyloxy)-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl)benzamide; 193 426.23-(2-morpholin-4-ylethoxy)-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1- yl)benzamide; 194 404.13-(pyridin-2-ylmethoxy)-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl)benzamide; 195 404.13-(pyridin-4-ylmethoxy)-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl)benzamide; 196 399.23-(2-isopropoxyethoxy)-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl)benzamide; 197 410.23-(2-pyrrolidin-2-ylethoxy)-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1- yl)benzamide; 198 411.23-(tetrahydro-2H-pyran-2-ylmethoxy)-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1- yl)benzamide; 199 397.23-(tetrahydro-2H-pyran-4-yloxy)-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1- yl)benzamide; 200 368.23-(butylamino)-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl)benzamide; 201 331.13-chloro-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl)benzamide; 202 393.13-(1H-imidazol-4-ylmethoxy)-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1- yl)benzamide; 203 418.22-[(4-methoxyphenyl)amino]-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1- yl)benzamide; 204 370.13-butoxy-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl)benzoic acid; 205 388.13-anilino-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl)benzamide; 206 402.23-(benzylamino)-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl)benzamide; 207 371.13-(3-hydroxypropoxy)-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl)benzamide; 208 385.23-(3-hydroxybutoxy)-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl)benzamide; 209 387.13-(2,3-dihydroxypropoxy)-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl)benzamide; 210 340.1N-butyl-4-(6,6-dimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indazol-1-yl)benzamide; 211 383.23-(2-methylbutoxy)-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl)benzamide; 212 383.23-(pentyloxy)-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl)benzamide; 213 383.23-(3-methylbutoxy)-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl)benzamide; 214 313.13-hydroxy-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl)benzamide; 215 360.14-(6,6-dimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indazol-1-yl)-N-phenylbenzamide; 216 394.22-(cyclohexylamino)-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl)benzamide; 217 395.23-(cyclohexyloxy)-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl)benzamide; 218 381.23-(pent-4-en-1-yloxy)-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl)benzamide; 219 432.12-(1,3-benzodioxol-5-ylamino)-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1- yl)benzamide; 220 396.22-(hexylamino)-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl)benzamide; 221 341.13-butoxy-4-(2-methyl-4-oxo-4,5,6,7-tetrahydro- 1H-indol-1-yl)benzamide;222 385.2 3-(4-hydroxybutoxy)-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl)benzamide; 223 397.23-[(3-methyloxetan-3-yl)methoxy]-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1- yl)benzamide; 224 384.23-(4-aminobutoxy)-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl)benzamide; 225 383.13-(tetrahydrofuran-3-yloxy)-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1- yl)benzamide; 226 397.23-(tetrahydrofuran-2-ylmethoxy)-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1- yl)benzamide; 227 381.23-[(1-ethylprop-2-en-1-yl)oxy]-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1- yl)benzamide; 228 3622-bromo-4-(6,6-dimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indazol-1-yl)benzamide; 229 409.13-(2-thienylmethoxy)-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl)benzamide; 230 283.14-(6,6-dimethyl-4-oxo-4,5,6,7-tetrahydro-1H- indol-1-yl)benzamide; 231390.1 2-[(methylsulfonyl)amino]-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl)benzamide; 232 354.12-(acetylamino)-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl)benzamide; 233 355.12-[(aminocarbonyl)amino]-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl)benzamide; 234 416.12-(benzoylamino)-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl)benzamide; 235 382.22-(butyrylamino)-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl)benzamide; 236 342.13-ethoxy-5-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl)pyridine-2- carboxamide; 237 389.12-(pyridin-3-ylamino)-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl)benzamide; 238 390.12-(pyridin-2-ylamino)-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl)benzoic acid; 239 432.22-[(3-ethoxyphenyl)amino]-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl)benzamide; 240 418.22-[(3-methoxyphenyl)amino]-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1- yl)benzamide; 241 356.13-butoxy-4-(6,6-dimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indazol-1-yl)benzamide; 242 371.23-butoxy-4-(6,6-dimethyl-4-oxo-4,5,6,7- tetrahydro-1H-indazol-1-yl)-N′-hydroxybenzenecarboximidamide; 243 326.1N′-hydroxy-3-methyl-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1- yl)benzenecarboximidamide; 244 311.13-methyl-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl)benzamide; 245 346.12-chloro-N-hydroxy-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1- yl)benzenecarboximidamide; 246 348.12,3-difluoro-N-hydroxy-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1- yl)benzenecarboximidamide; 247 355.18-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl)-2,3-dihydro-1,4-benzodioxine-5- carboxamide; 248 367.22-pentyl-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl)benzamide; 249 367.23-pentyl-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl)benzamide; 250 460.22-[(4-butoxyphenyl)amino]-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl)benzamide; 251 403.22-anilino-N′-hydroxy-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1- yl)benzenecarboximidamide; 252 472.12-{[4-(trifluoromethoxy)phenyl]amino}-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1- yl)benzamide; 253 440.12-[(2-chloro-4-fluorophenyl)amino]-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1- yl)benzamide; 254 436.12-[(2-chloro-4-methylphenyl)amino]-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1- yl)benzamide; 255 452.12-[(2-chloro-4-methoxyphenyl)amino]-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1- yl)benzamide; 256 448.22-[(3,4-dimethoxyphenyl)amino]-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1- yl)benzamide; 257 436.22-[(3-fluoro-4-methoxyphenyl)amino]-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1- yl)benzamide; 258 448.22-[(3,5-dimethoxyphenyl)amino]-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1- yl)benzamide; 259 448.22-[(2,5-dimethoxyphenyl)amino]-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1- yl)benzamide; 260 432.22-[(4-ethoxyphenyl)amino]-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl)benzamide; 261 406.12-[(4-fluorophenyl)amino]-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl)benzamide; 262 389.12-phenoxy-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl)benzamide; 263 405.12-(phenylthio)-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl)benzamide; 264 352.12-(cyclopropylamino)-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl)benzamide; 265 350.12-(prop-2-yn-1-ylamino)-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl)benzamide; 266 371.13-(propylthio)-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl)benzamide; 267 386.1N-hydroxy-3-(propylthio)-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1- yl)benzenecarboximidamide; 268 460.2N-[2-(aminocarbonyl)-5-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl)phenyl]-L- phenylalanine; 269 371.23-butoxy-4-[(4Z)-4-(hydroxyimino)-6,6-dimethyl-4,5,6,7-tetrahydro-1H-indazol-1-yl]benzamide; 270 469.32-(diethylamino)ethyl 3-butoxy-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1- yl)benzoate; 271 546.12-[(2-chloro-3,4,5-trimethoxyphenyl)amino]-4-(3-chloro-2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl)benzamide; 272 464.24-(6,6-dimethyl-4-oxo-4,5,6,7-tetrahydro-1H- indol-1-yl)-2-[(3,4,5-trimethoxyphenyl)amino]benzamide; 273 450.24-(2-methyl-4-oxo-4,5,6,7-tetrahydro-1H-indol- 1-yl)-2-[(3,4,5-trimethoxyphenyl)amino]benzamide; 274 442.12-[(3,4,5-trifluorophenyl)amino]-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1- yl)benzamide; 275 410.22-[(trans-4-hydroxycyclohexyl)amino]-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1- yl)benzamide; 276 408.22-[(4-oxocyclohexyl)amino]-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1- yl)benzamide; 277 402.22-[(4-methylphenyl)amino]-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl)benzamide; 278 428.22-(2,3-dihydro-1H-inden-4-ylamino)-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1- yl)benzamide; 279 430.22-[(2-propylphenyl)amino]-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl)benzamide; 280 430.22-[(2-isopropylphenyl)amino]-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1- yl)benzamide; 281 351.12-(3-hydroxyprop-1-yn-1-yl)-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1- yl)benzamide; 282 512.12-[(2-chloro-3,4,5-trimethoxyphenyl)amino]-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H- indol-1-yl)benzamide; 283331.1 4-(4-oxo-2-phenyl-4,5,6,7-tetrahydro-1H-indol- 1-yl)benzamide; 284442.1 2-[(2,4,5-trifluorophenyl)amino]-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1- yl)benzamide; 285 492.22-[(3,4,5-trimethoxybenzyl)amino]-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1- yl)benzamide; 286 406.12-[(2-fluorophenyl)amino]-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl)benzamide; 287 406.22-[(3-fluorophenyl)amino]-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl)benzamide; 288 420.22-[(4-fluoro-3-methylphenyl)amino]-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1- yl)benzamide; 289 434.22-[(3-hydroxy-4-methoxyphenyl)amino]-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1- yl)benzamide; 290 436.22-[(2-fluoro-4-methoxyphenyl)amino]-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1- yl)benzamide; 291 396.22-(tetrahydro-2H-pyran-4-ylamino)-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1- yl)benzamide; 292 424.12-[(2,4-difluorophenyl)amino]-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1- yl)benzamide; 293 424.12-[(3,4-difluorophenyl)amino]-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1- yl)benzamide; 294 445.22-anilino-4-{5-[(dimethylamino)methyl]-2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1- yl}benzamide; 295 346.14-[(4E)-4-(hydroxyimino)-2-phenyl-4,5,6,7-tetrahydro-1H-indol-1-yl]benzamide; 296 494.22-{[4-(benzyloxy)phenyl]amino}-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1- yl)benzamide; 297 396.22-[(tetrahydrofuran-2-ylmethyl)amino]-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1- yl)benzamide; 298 398.22-[(1,3-dioxolan-2-ylmethyl)amino]-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1- yl)benzamide; 299 384.22-[(2-methoxy-1-methylethyl)amino]-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1- yl)benzamide; 300 400.22-{[2-(2-hydroxyethoxy)ethyl]amino}-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1- yl)benzamide; 301 356.12-[(4-hydroxybutyl)amino]-4-(2-methyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl)benzamide; 302 411.24-(2-methyl-4-oxo-4,5,6,7-tetrahydro-1H-indol- 1-yl)-2-[(3-morpholin-4-ylpropyl)amino]benzamide; 303 403.22-[(pyridin-2-ylmethyl)amino]-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1- yl)benzamide; 304 503.22-{[2-(diethylamino)-4-ethoxyphenyl]amino}-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H- indol-1-yl)benzamide; 305454.1 2-{[4-(difluoromethoxy)phenyl]amino}-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1- yl)benzamide; 306 462.22-[(3,4-dimethoxybenzyl)amino]-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1- yl)benzamide; 307 370.22-[(3-hydroxypropyl)amino]-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1- yl)benzamide; 308 352.12-(allylamino)-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl)benzamide; 309 493.24-[(4E)-4-(hydroxyimino)-2,6,6-trimethyl-4,5,6,7-tetrahydro-1H-indol-1-yl]-2-[(3,4,5-trimethoxyphenyl)amino]benzamide; 310 384.22-[(3-methoxypropyl)amino]-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1- yl)benzamide; 311 389.12-(pyridin-4-ylamino)-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl)benzamide; 312 420.22-{[3-(1H-imidazol-1-yl)propyl]amino}-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1- yl)benzamide; 313 406.22-{[2-(1H-imidazol-1-yl)ethyl]amino}-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1- yl)benzamide; 314 379.12-(isoxazol-3-ylamino)-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl)benzamide; 315 403.22-[(pyridin-3-ylmethyl)amino]-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1- yl)benzamide; 316 340.14-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H- indol-1-yl)phthalamide;317 348 3-bromo-N′-hydroxy-4-(4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl)benzenecarboximidamide; 318 342.14-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H- indol-1-yl)phthalicacid; 319 467.3 2-[(10-aminodecyl)amino]-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl)benzamide; 320 324.12-(allylamino)-4-(2-methyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl)benzamide; 321 386.12-(2,3-dihydro-1H-inden-1-ylamino)-4-(4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl)benzamide; 322 338.12-(cyclopropylamino)-4-(2,3-dimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl)benzamide; 323 342.12-[(2-methoxyethyl)amino]-4-(2-methyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl)benzamide; 324 324.13-[(cyclopropylmethyl)amino]-4-(4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl)benzamide; 325 492.22-{[3-(3-hydroxypropoxy)-4-methoxyphenyl]amino}-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl)benzamide; 326 324.12-(allylamino)-4-(3-methyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl)benzamide; 327 324.12-(cyclopropylamino)-4-(3-methyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl)benzamide; 328 342.12-[(2-methoxyethyl)amino]-4-(3-methyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl)benzamide; 329 269.14-(2-methyl-4-oxo-4,5,6,7-tetrahydro-1H-indol- 1-yl)benzamide; 330 297.14-(3-ethyl-2-methyl-4-oxo-4,5,6,7-tetrahydro- 1H-indol-1-yl)benzamide;331 269.1 4-(3-methyl-4-oxo-4,5,6,7-tetrahydro-1H-indol- 1-yl)benzamide;332 487.2 2-[(2-{2-[2-(2- aminoethoxy)ethoxy]ethoxy}ethyl)amino]-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H- indol-1-yl)benzamide; 333382.2 2-[(trans-4-hydroxycyclohexyl)amino]-4-(2-methyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1- yl)benzamide; 334 297.14-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H- indol-1-yl)benzamide;335 360.1 2-anilino-4-(3-methyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl)benzamide; 336 382.22-[(trans-4-hydroxycyclohexyl)amino]-4-(3-methyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1- yl)benzamide; 337 396.24-(2,3-dimethyl-4-oxo-4,5,6,7-tetrahydro-1H- indol-1-yl)-2-[(trans-4-hydroxycyclohexyl)amino]benzamide; 338 374.12-anilino-4-(2,3-dimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl)benzamide; 339 450.24-(3-methyl-4-oxo-4,5,6,7-tetrahydro-1H-indol- 1-yl)-2-[(3,4,5-trimethoxyphenyl)amino]benzamide; 340 383.22-{[2-(dimethylamino)ethyl]amino}-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1- yl)benzamide; 341 355.22-{[2-(dimethylamino)ethyl]amino}-4-(3-methyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1- yl)benzamide; 342 395.22-(piperidin-4-ylamino)-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl)benzamide; 343 298.14-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H- indazol-1-yl)benzamide;344 333 2-bromo-5-(4-oxo-4,5,6,7-tetrahydro-1H-indol-1- yl)benzamide;345 410.2 2-[(trans-4-hydroxycyclohexyl)amino]-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1- yl)benzamide; 346 409.22-[(1-methylpiperidin-4-yl)amino]-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1- yl)benzamide; 347 453.2(4-{[2-(aminocarbonyl)-5-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1- yl)phenyl]amino}piperidin-1-yl)aceticacid; 348 370.2 2-[(2-methoxyethyl)amino]-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl)benzamide; 349 403.22-[(pyridin-4-ylmethyl)amino]-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1- yl)benzamide; 350 396.22-(tetrahydro-2H-pyran-4-ylamino)-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1- yl)benzamide; 351 478.22-[(3,4,5-trimethoxyphenyl)amino]-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1- yl)benzamide; 352 340.14-(3-isobutyl-6,6-dimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indazol-1-yl)benzamide; 353 312.12-amino-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl)benzamide; 354 352.12-(allylamino)-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl)benzamide; 355 409.22-[(1-methylpiperidin-4-yl)amino]-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1- yl)benzamide; 356 395.22-(piperidin-4-ylamino)-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl)benzamide; 357 369.23-butoxy-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl)benzamide; 358 428.22-(2,3-dihydro-1H-inden-1-ylamino)-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1- yl)benzamide; 359 408.22-[(4-oxocyclohexyl)amino]-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1- yl)benzamide; 360 355.12-[(aminocarbonyl)amino]-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl)benzamide; 361 397.22-(tetrahydro-2H-pyran-4-ylamino)-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indazol- 1-yl)benzamide; 362 3762-bromo-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indazol-1-yl)benzamide; 363 440.22-[(3-morpholin-4-ylpropyl)amino]-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indazol- 1-yl)benzamide; 364 397.22-[(tetrahydrofuran-2-ylmethyl)amino]-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indazol- 1-yl)benzamide; 365 523.32-{[trans-4-(2-morpholin-4-ylethoxy)cyclohexyl]amino}-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1- yl)benzamide; 366 435.22-[(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)amino]-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl)benzamide; 367 312.14-(3-ethyl-6,6-dimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indazol-1-yl)benzamide; 368 394.22-(cyclohexylamino)-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl)benzamide; 369 410.22-[(1-methylpiperidin-4-yl)amino]-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indazol- 1-yl)benzamide; 370 353.12-(cyclopropylamino)-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indazol-1-yl)benzamide; 371 352.12-(cyclopropylamino)-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl)benzamide; 372 366.22-[(cyclopropylmethyl)amino]-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1- yl)benzamide; 373 448.22-[(3,4-dimethoxyphenyl)amino]-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1- yl)benzamide; 374 449.22-[(3,4-dimethoxyphenyl)amino]-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indazol- 1-yl)benzamide; 375 479.22-[(3,4,5-trimethoxyphenyl)amino]-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indazol- 1-yl)benzamide; 376 519.22-({3-[3-(dimethylamino)propoxy]-4-methoxyphenyl}amino)-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl)benzamide; 377 411.22-[(trans-4-hydroxycyclohexyl)amino]-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indazol- 1-yl)benzamide; 378 409.22-[(4-oxocyclohexyl)amino]-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indazol-1- yl)benzamide; 379 412.12-{[2-(aminocarbonyl)-5-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl)phenyl]amino}- 2-oxoethyl acetate; 380385.2 2-[(3-methoxypropyl)amino]-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indazol-1- yl)benzamide; 381 421.22-{[3-(1H-imidazol-1-yl)propyl]amino}-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indazol- 1-yl)benzamide; 382 467.2Trans-4-{[2-(aminocarbonyl)-5-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1- yl)phenyl]amino}cyclohexylglycinate; 383 355.2 2-[(2-aminoethyl)amino]-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl)benzamide; 384 452.2Trans-4-{[2-(aminocarbonyl)-5-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1- yl)phenyl]amino}cyclohexyl acetate;385 383.2 4-(3-ethyl-4-oxo-4,5,6,7-tetrahydro-1H-indazol-1-yl)-2-[(tetrahydrofuran-2- ylmethyl)amino]benzamide; 386 413.22-[(1,4-dioxan-2-ylmethyl)amino]-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indazol- 1-yl)benzamide; 387 393.12-[(2-furylmethyl)amino]-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indazol-1- yl)benzamide; 388 392.12-[(2-furylmethyl)amino]-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl)benzamide; 389 425.22-[(2-piperazin-1-ylethyl)amino]-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indazol- 1-yl)benzamide; 390 424.22-[(2-piperazin-1-ylethyl)amino]-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1- yl)benzamide; 391 506.22-({3-[2-(dimethylamino)ethoxy]-4-methoxyphenyl}amino)-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indazol-1-yl)benzamide; 392 352.14-[6,6-dimethyl-4-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]benzamide; 393 353.12-(allylamino)-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indazol-1-yl)benzamide; 394 468.2Trans-4-{[2-(aminocarbonyl)-5-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indazol-1- yl)phenyl]amino}cyclohexylglycinate; 395 411.2 2-[(cis-4-hydroxycyclohexyl)amino]-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indazol- 1-yl)benzamide; 396 3244-[4-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]benzamide; 397 398.24-(3-ethyl-4-oxo-4,5,6,7-tetrahydro-1H-indazol-1-yl)-N′-hydroxy-2-[(tetrahydrofuran-2-ylmethyl)amino]benzenecarboximidamide; 398 424.22-{[2-(1-methylpyrrolidin-2-yl)ethyl]amino}-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H- indazol-1-yl)benzamide;399 423.2 2-{[2-(1-methylpyrrolidin-2-yl)ethyl]amino}-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H- indol-1-yl)benzamide; 400384.2 2-{[2-(dimethylamino)ethyl]amino}-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indazol- 1-yl)benzamide; 401 495.2Trans-4-{[2-(aminocarbonyl)-5-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1- yl)phenyl]amino}cyclohexyl N,N-dimethylglycinate; 402 332.1 3-chloro-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indazol-1-yl)benzamide; 403 299.14-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H- indazol-1-yl)benzoicacid; 404 390.1 2-(pyridin-3-ylamino)-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indazol-1-yl)benzamide; 405 407.12-(pyridin-4-ylthio)-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indazol-1-yl)benzamide; 406 452.22-[(1-glycylpiperidin-4-yl)amino]-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1- yl)benzamide; 407 314.1N-hydroxy-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indazol-1-yl)benzamide; 408 356.1N-(2-methoxyethyl)-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indazol-1-yl)benzamide; 409 416.22-{[(1R)-1-phenylethyl]amino}-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1- yl)benzamide; 410 423.22-[(1-ethylpiperidin-3-yl)amino]-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1- yl)benzamide; 411 416.22-{[(1S)-1-phenylethyl]amino}-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1- yl)benzamide; 412 417.22-{[(1S)-1-phenylethyl]amino}-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indazol- 1-yl)benzamide; 413 424.22-[(trans-4-methoxycyclohexyl)amino]-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1- yl)benzamide; 414 438.22-{[3-(2-oxopyrrolidin-1-yl)propyl]amino}-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H- indazol-1-yl)benzamide;415 574.2 2-({3-[3-(dimethylamino)propoxy]-4-methoxyphenyl}amino)-4-[6,6-dimethyl-4-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H- indazol-1-yl]benzamide; 416447.1 2-(2,1,3-benzothiadiazol-4-ylamino)-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indazol- 1-yl)benzamide; 417 423.12-[(3-chlorophenyl)amino]-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indazol-1- yl)benzamide; 418 419.22-[(3-methoxyphenyl)amino]-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indazol-1- yl)benzamide; 419 477.22-({2-[2-(dimethylamino)ethoxy]pyridin-4-yl}amino)-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indazol-1-yl)benzamide; 420 465.24-[6,6-dimethyl-4-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]-2-[(trans-4-hydroxycyclohexyl)amino]benzamide; 421 451.14-[6,6-dimethyl-4-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]-2-(tetrahydro-2H-pyran-4-ylamino)benzamide; 422 445.22-{[(1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]amino}-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indazol-1-yl)benzamide; 423 445.22-{[(1R,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]amino}-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indazol-1-yl)benzamide; 424 433.13-{[2-(aminocarbonyl)-5-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indazol-1- yl)phenyl]amino}benzoic acid; 425 496.2Trans-4-{[2-(aminocarbonyl)-5-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indazol-1- yl)phenyl]amino}cyclohexyl N,N-dimethylglycinate; 426 430.12-[(1-oxidotetrahydro-2H-thiopyran-4-yl)oxy]-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H- indazol-1-yl)benzamide;427 446.1 2-[(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)oxy]-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indazol-1-yl)benzamide; 428 382.24-(3-methyl-4-oxo-5,6,7,8- tetrahydrocyclohepta[b]pyrrol-1(4H)-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide; 429 387.12-{[2-(methylthio)ethyl]amino}-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indazol- 1-yl)benzamide; 430 560.22-({3-[2-(dimethylamino)ethoxy]-4-methoxyphenyl}amino)-4-[6,6-dimethyl-4-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H- indazol-1-yl]benzamide; 431531.2 2-({2-[2-(dimethylamino)ethoxy]pyridin-4-yl}amino)-4-[6,6-dimethyl-4-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H- indazol-1-yl]benzamide; 432511.2 Trans-4-{[2-(aminocarbonyl)-5-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indazol-1-yl)phenyl]amino}cyclohexyl(acetyloxy)acetate; 433 413.12-(tetrahydro-2H-thiopyran-4-ylamino)-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indazol- 1-yl)benzamide; 434 429.12-[(1-oxidotetrahydro-2H-thiopyran-4-yl)amino]-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H- indazol-1-yl)benzamide;435 445.2 2-[(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)amino]-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indazol-1-yl)benzamide; 436 432.22-{[3-(aminocarbonyl)phenyl]amino}-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indazol- 1-yl)benzamide; 437 379.22-(cyclopent-3-en-1-ylamino)-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indazol- 1-yl)benzamide; 438 395.12-[(2,2,2-trifluoroethyl)amino]-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indazol- 1-yl)benzamide; 439 413.22-{[(3R,4S)-3,4-dihydroxycyclopentyl]amino}-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H- indazol-1-yl)benzamide;440 420.2 2-[(6-methoxypyridin-3-yl)amino]-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indazol- 1-yl)benzamide; 441 420.22-[(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)amino]-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indazol-1-yl)benzamide; 442 483.2Trans-4-{[2-(aminocarbonyl)-5-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indazol-1- yl)phenyl]amino}cyclohexylmethoxyacetate; 443 491.2 2-({1-[3-(dimethylamino)propyl]-6-oxo-1,6-dihydropyridin-3-yl}amino)-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indazol-1- yl)benzamide; 444 424.22-{[2-(2-oxopyrrolidin-1-yl)ethyl]amino}-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H- indazol-1-yl)benzamide;445 473.1 2-{[3-(trifluoromethoxy)phenyl]amino}-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indazol- 1-yl)benzamide; 446 433.24-[3-(difluoromethyl)-6,6-dimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indazol-1-yl]-2-(tetrahydro-2H-pyran-4-ylamino)benzamide; 447 447.24-[3-(difluoromethyl)-6,6-dimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indazol-1-yl]-2-[(trans-4-hydroxycyclohexyl)amino]benzamide; 448 467.14-[6,6-dimethyl-4-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]-2-(tetrahydro-2H-thiopyran-4-ylamino)benzamide; 449 449.14-[3-(difluoromethyl)-6,6-dimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indazol-1-yl]-2-(tetrahydro-2H-thiopyran-4-ylamino)benzamide; 450 385.22-[(2-methoxy-1-methylethyl)amino]-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indazol- 1-yl)benzamide; 451 460.2N-(2-aminophenyl)-3-butoxy-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1- yl)benzamide; 452 410.22-{[(3S)-6-oxopiperidin-3-yl]amino}-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indazol- 1-yl)benzamide; 453 482.2Trans-4-{[2-(aminocarbonyl)-5-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indazol-1- yl)phenyl]amino}cyclohexylL-alaninate; 454 482.2 Trans-4-{[2-(aminocarbonyl)-5-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indazol-1- yl)phenyl]amino}cyclohexylD-alaninate; 455 481.2 Trans-4-{[2-(aminocarbonyl)-5-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1- yl)phenyl]amino}cyclohexylL-alaninate; 456 481.2 Trans-4-{[2-(aminocarbonyl)-5-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1- yl)phenyl]amino}cyclohexylD-alaninate; 457 427.1 1-[4-(aminocarbonyl)-3-(tetrahydro-2H-pyran-4-ylamino)phenyl]-6,6-dimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indazole-3-carboxylic acid; 458 475.15-bromo-2-[(tetrahydrofuran-2-ylmethyl)amino]-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H- indazol-1-yl)benzamide;459 411.2 2-[(3-hydroxycyclohexyl)amino]-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indazol- 1-yl)benzamide; 460 439.24-{[2-(aminocarbonyl)-5-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indazol-1- yl)phenyl]amino}cyclohexanecarboxylicacid; 461 522.2 Trans-4-({2-(aminocarbonyl)-5-[6,6-dimethyl-4-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}amino)cyclohexyl glycinate; 462 509.3Trans-4-{[2-(aminocarbonyl)-5-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1- yl)phenyl]amino}cyclohexylL-valinate; 463 429.2 2-[(2,6-dihydroxytetrahydro-2H-pyran-4-yl)amino]-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indazol-1-yl)benzamide; 464 433.12-(cyclopent-3-en-1-ylamino)-4-[6,6-dimethyl-4-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H- indazol-1-yl]benzamide;465 445.2 4-[3-(difluoromethyl)-6,6-dimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indazol-1-yl]-2-[(4-oxocyclohexyl)amino]benzamide; 466 463.14-[6,6-dimethyl-4-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]-2-[(4-oxocyclohexyl)amino]benzamide; 467 483.14-[6,6-dimethyl-4-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]-2-[(1-oxidotetrahydro-2H-thiopyran-4- yl)amino]benzamide; 468 465.14-[3-(difluoromethyl)-6,6-dimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indazol-1-yl]-2-[(1-oxidotetrahydro-2H-thiopyran-4- yl)amino]benzamide; 469 393.22-(cyclohex-3-en-1-ylamino)-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indazol-1- yl)benzamide; 470 427.22-{[(3S,4R)-3,4-dihydroxycyclohexyl]amino}-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H- indazol-1-yl)benzamide;471 473.1 2-{[4-(trifluoromethoxy)phenyl]amino}-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indazol- 1-yl)benzamide; 472 504.2trans-4-({2-(aminocarbonyl)-5-[3-(difluoromethyl)-6,6-dimethyl-4-oxo-4,5,6,7- tetrahydro-1H-indazol-1-yl]phenyl}amino)cyclohexyl glycinate; 473 467.14-[6,6-dimethyl-4-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]-2-[(3-ethynylphenyl)amino]benzamide; 474 383.24-(6,6-dimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indazol-1-yl)-2-(tetrahydro-2H-pyran-4- ylamino)benzamide; 475 492.24-[6,6-dimethyl-4-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]-2-{[3-(2-oxopyrrolidin-1-yl)propyl]amino}benzamide; 476 365.14-(trifluoromethyl)-3-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl)benzamide; 477 465.24-[6,6-dimethyl-4-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]-2-[(cis-4-hydroxycyclohexyl)amino]benzamide; 478 435.12-{[3-(methylthio)phenyl]amino}-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indazol- 1-yl)benzamide; 479 366.14-(trifluoromethyl)-3-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indazol-1-yl)benzamide; 480 338.13-(3-methyl-4-oxo-4,5,6,7-tetrahydro-1H-indazol-1-yl)-4-(trifluoromethyl)benzamide; 481 465.22-[6,6-dimethyl-4-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]-4-[(trans-4-hydroxycyclohexyl)amino]benzamide; 482 450.24-[6,6-dimethyl-4-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]-2- (piperidin-4-ylamino)benzamide;483 492.2 2-[(1-acetylpiperidin-4-yl)amino]-4-[6,6-dimethyl-4-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]benzamide; 484 540.22-[(1-benzylpiperidin-4-yl)amino]-4-[6,6-dimethyl-4-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]benzamide; 485 521.24-({2-(aminocarbonyl)-5-[6,6-dimethyl-4-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H- indazol-1-yl]phenyl}amino)-N,N-dimethylpiperidine-1-carboxamide; 486 4452-bromo-4-[6,6-dimethyl-4-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]-N′-hydroxybenzenecarboximidamide; 487 526.22-[(1-benzylpyrrolidin-3-yl)amino]-4-[6,6-dimethyl-4-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]benzamide; 488 526.24-[6,6-dimethyl-4-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]-2-[(1-phenylpiperidin-4-yl)amino]benzamide; 489 524.2({[(4E)-1-[4-(aminocarbonyl)-3-(tetrahydro-2H-pyran-4-ylamino)phenyl]-6,6-dimethyl-3-(trifluoromethyl)-1,5,6,7-tetrahydro-4H-indazol-4-ylidene]amino}oxy)acetic acid; 490 471.14-[6,6-dimethyl-4-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]-2-{[2- hydroxy-1,1-bis(hydroxymethyl)ethyl]amino}benzamide; 491 437.14-[6,6-dimethyl-4-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]-2-[(3R)-tetrahydrofuran-3-ylamino]benzamide; 492 536.2trans-4-({2-(aminocarbonyl)-5-[6,6-dimethyl-4-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}amino)cyclohexyl L- alaninate; methanesulfonate 493564.2 trans-4-({2-(aminocarbonyl)-5-[6,6-dimethyl-4-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}amino)cyclohexyl L-valinate methanesulfonate; 494505.2 2-[allyl(trans-4-hydroxycyclohexyl)amino]-4-[6,6-dimethyl-4-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]benzamide; 495 536.22-Amino-propionic acid trans-4-[2-carbamoyl-5-(6,6-dimethyl-4-oxo-3-trifluoromethyl-4,5,6,7-tetrahydro-indazol-1-yl)-phenylamino]- cyclohexyl ester; 496 513.24-[6,6-dimethyl-4-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]-2-(4-pyridin-2-ylpiperazin-1-yl)benzamide; 497 539.22-[(2,3-dihydroxypropyl)(trans-4-hydroxycyclohexyl)amino]-4-[6,6-dimethyl-4-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H- indazol-1-yl]benzamide; 498507.2 4-[6,6-dimethyl-4-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]-2-[(trans- 4-hydroxycyclohexyl)(2-oxoethyl)amino]benzamide; 499 441.12-[(2,3-dihydroxypropyl)amino]-4-[6,6-dimethyl-4-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydro- 1H-indazol-1-yl]benzamide;500 442.1 2-[(2,3-dihydroxypropyl)amino]-4-[6,6-dimethyl-4-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydro- 1H-indazol-1-yl]benzoicacid; 501 597.2 2-(acetoxymethyl)-2-(2-carbamoyl-5-(6,6-dimethyl-4-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)phenylamino)propane- 1,3-diyl diacetate; 502555.2 2-({2-(aminocarbonyl)-5-[6,6-dimethyl-4-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H- indazol-1-yl]phenyl}amino)-2-(hydroxymethyl)propane-1,3-diyl diacetate; 503 513.12-({2-(aminocarbonyl)-5-[6,6-dimethyl-4-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}amino)-3-hydroxy-2- (hydroxymethyl)propyl acetate;504 509.2 4-[6,6-dimethyl-4-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]-2-[(trans- 4-hydroxycyclohexyl)(2-hydroxyethyl)amino]benzamide; 505 555.12-({4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}amino)-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indazol- 1-yl)benzamide; 506 550.32-({1-[3-(4-methylpiperazin-1-yl)propanoyl]piperidin-4-yl}amino)-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indazol- 1-yl)benzamide; 507 501.22-[(1-isonicotinoylpiperidin-4-yl)amino]-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H- indazol-1-yl)benzamide;508 501.2 2-{[1-(pyridin-3-ylcarbonyl)piperidin-4-yl]amino}-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indazol-1-yl)benzamide; 509 422.22-(1-azabicyclo[2.2.2]oct-3-ylamino)-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indazol- 1-yl)benzamide; 510 460.12-{[(3R)-1-(methylsulfonyl)pyrrolidin-3-yl]amino}-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indazol-1-yl)benzamide; 511 467.22-[(1-beta-alanylpiperidin-4-yl)amino]-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H- indazol-1-yl)benzamide;512 493.2 2-[(1-prolylpiperidin-4-yl)amino]-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indazol- 1-yl)benzamide; 513 424.22-{[(3R)-1-acetylpyrrolidin-3-yl]amino}-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H- indazol-1-yl)benzamide;514 453.2 (3R)-3-{[2-(aminocarbonyl)-5-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indazol-1-yl)phenyl]amino}-N,N-dimethylpyrrolidine-1- carboxamide; 515 523.2[[2-Carbamoyl-5-(6,6-dimethyl-4-oxo-3-trifluoromethyl-4,5,6,7-tetrahydro-indazol-1-yl)-phenyl]-(trans-4-hydroxy-cyclohexyl)- amino]-acetic acid; 516 419.22-{[4-(hydroxymethyl)phenyl]amino}-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indazol- 1-yl)benzamide; 517 451.14-[6,6-dimethyl-4-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]-2-{[(1R,3S)-3-hydroxycyclopentyl]amino}benzamide; 518 451.14-[6,6-dimethyl-4-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]-2-{[(1R,3R)-3-hydroxycyclopentyl]amino}benzamide; 519 397.22-{[(2R)-tetrahydrofuran-2-ylmethyl]amino}-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H- indazol-1-yl)benzamide;520 505.2 2-{[trans-4-(allyloxy)cyclohexyl]amino}-4-[6,6-dimethyl-4-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]benzamide; 521 397.22-{[(2S)-tetrahydrofuran-2-ylmethyl]amino}-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H- indazol-1-yl)benzamide;522 473.2 2-[(1-isonicotinoylazetidin-3-yl)amino]-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H- indazol-1-yl)benzamide;523 473.2 2-{[1-(pyridin-3-ylcarbonyl)azetidin-3-yl]amino}-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indazol-1-yl)benzamide; 524 509.22-{[1-(3-morpholin-4-ylpropanoyl)azetidin-3-yl]amino}-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indazol-1-yl)benzamide; 525 522.32-({1-[3-(4-methylpiperazin-1-yl)propanoyl]azetidin-3-yl}amino)-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indazol- 1-yl)benzamide; 526 401.12-{[3-(methylthio)propyl]amino}-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indazol- 1-yl)benzamide; 527 437.12-[6,6-dimethyl-4-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]-4-[(3R)-tetrahydrofuran-3-ylamino]benzamide; 528 385.22-{[(1S)-2-methoxy-1-methylethyl]amino}-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H- indazol-1-yl)benzamide;529 396.2 2-(tetrahydro-2H-pyran-2-ylamino)-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1- yl)benzamide; 530 655.32-[[trans-4-(allyloxy)cyclohexyl](3,5-dimethoxybenzyl)amino]-4-[6,6-dimethyl-4-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H- indazol-1-yl]benzamide; 531689.3 2-[[trans-4-(2,3- dihydroxypropoxy)cyclohexyl](3,5-dimethoxybenzyl)amino]-4-[6,6-dimethyl-4-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H- indazol-1-yl]benzamide; 532404.1 4-{3-[(benzyloxy)methyl]-6,6-dimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indazol-1-yl}benzamide; 533 448.22-({2-[(dimethylamino)sulfonyl]ethyl}amino)-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H- indazol-1-yl)benzamide;534 382.2 2-[(3S)-pyrrolidin-3-ylamino]-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indazol- 1-yl)benzamidehydrochloride; 535 424.2 2-{[(3S)-1-acetylpyrrolidin-3-yl]amino}-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H- indazol-1-yl)benzamide;536 507.2 4-[6,6-dimethyl-4-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]-2-{[trans-4-(2-oxoethoxy)cyclohexyl]amino}benzamide; 537 539.22-{[4-(2,3-dihydroxypropoxy)cyclohexyl]amino}-4-[6,6-dimethyl-4-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]benzamide; 538 516.14-[6,6-dimethyl-4-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]-2-({2-[(isopropylsulfonyl)amino]ethyl}amino)benzamide; 539 509.24-[6,6-dimethyl-4-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]-2-{[trans-4-(2-hydroxyethoxy)cyclohexyl]amino}benzamide; 540 523.2{[trans-4-({2-(aminocarbonyl)-5-[6,6-dimethyl-4-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydro- 1H-indazol-1-yl]phenyl}amino)cyclohexyl]oxy}acetic acid; 541 550.14-[6,6-dimethyl-4-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]-2-({2-[(phenylsulfonyl)amino]ethyl}amino)benzamide; 542 490.22-{[2-(morpholin-4-ylsulfonyl)ethyl]amino}-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H- indazol-1-yl)benzamide;543 327.1 4-[3-(2-aminoethyl)-6,6-dimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indazol-1-yl]benzamide; 544 451.12-[6,6-dimethyl-4-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]-4- {methyl[(3R)-tetrahydrofuran-3-yl]amino}benzamide; 545 439.1 2-[6,6-dimethyl-4-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]-4-[(2-methoxy-1-methylethyl)amino]benzamide; 546 4304-bromo-2-[6,6-dimethyl-4-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H- indazol-1-yl]benzamide; 547425.2 4-(3-ethyl-6,6-dimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indazol-1-yl)-2-[(trans-4-hydroxycyclohexyl)amino]benzamide; 548 522.24-[6,6-dimethyl-4-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]-2-[(trans- 4-{[(2E)-2-(hydroxyimino)ethyl]oxy}cyclohexyl)amino]benzamide; 549 453.22-[(trans-4-hydroxycyclohexyl)amino]-4-(3-isobutyl-6,6-dimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indazol-1-yl)benzamide; 550 437.24-(3-cyclopropyl-6,6-dimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indazol-1-yl)-2-[(trans-4-hydroxycyclohexyl)amino]benzamide; 551 426.24-[3-(aminomethyl)-6,6-dimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indazol-1-yl]-2-[(trans-4-hydroxycyclohexyl)amino]benzamide methanesulfonate (salt); 552 452.22-[(1-methyl-2-oxo-2-piperidin-1-ylethyl)amino]-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indazol-1-yl)benzamide; 553 440.24-[3-(2-aminoethyl)-6,6-dimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indazol-1-yl]-2-[(trans-4-hydroxycyclohexyl)amino]benzamide; 554 439.22-[(trans-4-hydroxycyclohexyl)amino]-4-(3-isopropyl-6,6-dimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indazol-1-yl)benzamide; 555 437.12-[6,6-dimethyl-4-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]-4-(tetrahydrofuran-3-ylamino)benzamide; 556 451.24-[3-(cyclopropylmethyl)-6,6-dimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indazol-1-yl]-2-[(trans-4-hydroxycyclohexyl)amino]benzamide; 557 424.22-[(trans-4-hydroxycyclohexyl)amino]-4-(2,3,6,6-tetramethyl-4-oxo-4,5,6,7-tetrahydro- 1H-indol-1-yl)benzamide;558 338.1 4-[3-(cyclopropylmethyl)-6,6-dimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indazol-1-yl]benzamide; 559 398.22-{[2-(dimethylamino)-2-oxoethyl]amino}-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H- indazol-1-yl)benzamide;

Example 47

Additional compounds of the invention are represented by Formula XXIIIand have substituents R₃, R₄, R₅, R₆, R₇, Q₁, Q₂, Q₃, Y, X₁, and X₂ aslisted in the tables below. These compounds are prepared essentiallyaccording to the procedures set forth in Schemes 1-9 above and describedin the above examples.

TABLE A1 Substructures and codes for R₃, R₄ 001

002

003

004

005

006

007

010

011

012

013

014

015

016

017

018

019

020

021

022

023

024

030

031

032

033

034

035

036

040

041

042

043

044

045

046

050

051

052

053

054

055

060

061

062

063

064

065

070

071

072

073

074

075

076

080

081

082

083

084

085

TABLE A2 Substructures and codes for R₃, R₄ 110

111

112

113

114

120

121

122

123

TABLE A3 Substructures and codes for R₃, R₄ 140

141

142

142

144

150

151

152

153

154

155

160

161

162

163

164

170

172

173

174

175

176

180

181

182

183

184

185

190

191

TABLE A4 Substructures and codes for R₃, R₄ 210

211

212

213

214

220

221

222

223

224

TABLE A5 Substructures and codes for R₃, R₄ 240

241

242

243

244

250

251

252

253

254

255

256

260

261

262

263

264

270

271

272

273

274

275

280

281

282

283

284

285

TABLE A6 Substructures and codes for R₃, R₄ 300

301

302

303

310

311

312

313

320

321

322

323

324

330

331

332

333

340

341

342

343

344

350

351

352

353

354

355

360

361

362

363

364

370

371

372

373

374

375

380

381

382

383

384

390

391

392

393

394

395

TABLE A7 Substructures and codes for R₃, R₄ 410

411

412

413

420

421

422

423

424

425

430

431

432

433

434

TABLE A8 Substructures and codes for R₃, R₄ 450

451

452

453

454

455

456

460

461

462

463

464

465

470

471

472

473

474

475

480

481

482

483

484

485

486

490

491

492

493

494

500

501

502

503

504

505

TABLE A9 Substructures and codes for R₃, R₄ 520

521

522

523

524

525

530

531

532

533

534

540

541

542

543

544

550

551

552

553

554

555

560

561

562

563

564

565

570

571

572

573

574

580

581

582

583

584

585

586

587

TABLE B Substructures and codes for Q₂, Q₁, Q₃ B00 N B01 C—H B02 C—C≡NB03 C—CH₃ B04 C—NH₂ B05 C—CH₂CH₃ B06 C—CF₃ B07 C—Br B08 C—Cl B09 C—F B10

B11

B12

B13

B14

B15

B16

B17

B20

B21

B22

B23

B24

B25

B30

B31

B32

B33

B34

B35

B40

B41

B42

B43

B44

B45

TABLE C Substructures and codes for X₁, Y C00 N C01 C—H C02 C—CF₃ C03C—CHF₂ C04 C—CH₂F C05 C—C≡N C06 C—NO₂ C07 C—Cl C08 C—Br C09

C10 C—C≡CH C20

C21

C22

C23

C24

C25

C26

C27

C28

C29

C30

C31

C32

C33

C34

C35

C36

C37

TABLE D Substructures and codes for R₇ D00

D01

D02

D03

D04

D05

D06

D07 O D08 S D10

D11

D12

TABLE E Substructures and codes for X₂ (R₅, R₆) E00

E01

E02

E03

E04

E05

E10

E11

E12

E13

E14

E15

Biological Evaluation Example 48 Cell Proliferation Assays

A panel of cancer cell lines was obtained from the DCTP TumorRepository, National Cancer Institute (Frederick, Md.) or ATCC(Rockville, Md.). Cell cultures were maintained in Hyclone RPMI 1640medium (Logan, Utah) supplemented with 10% fetal bovine serum and 20 mMHEPES buffer, final pH 7.2, at 37° C. with a 5% CO₂ atmosphere. Cultureswere maintained at sub-confluent densities. Human umbilical veinendothelial cells (HUVEC) were purchased from Clonetics, a division ofCambrex (Walkersville, Md.). Cultures were established fromcryopreserved stocks using Clonetics EGM-2 medium supplemented with 20mM HEPES, final pH 7.2, at 37° C. with a 5% CO₂ atmosphere.

For proliferation assays, cells were seeded with the appropriate mediuminto 96 well plates at 1,000-2,500 cells per well, depending on the cellline, and were incubated overnight. The following day, test compound,DMSO solution (negative control), or Actinomycin D (positive control)was added to the appropriate wells as 10× concentrated stocks preparedin phosphate buffered saline. The cell plates were then incubated for anadditional 2-5 days, depending on the cell line, to allow proliferationto occur. To measure cell density, 50 μL of WST-1 solution (RocheApplied Science, Ind.) diluted 1:5 in phosphate buffered saline wasadded to each well, and the cells incubated for an additional 1-5 hrs.,again depending on the cell line. Optical density was determined foreach well at 450 nM using a Tecan GeniosPro plate reader (RTP, NC). Thepercentage of cell growth was determined by comparing the cell growth inthe presence of test compounds to the cells treated with DMSO vehicle(control, 100% growth) and cells treated with Actinomycin D (10 μM, 0%growth).

Immediately after the WST-1 determination, the medium was removed fromthe PC-3, NCI-H460 and HUVEC cell lines, and the plates stored at −80°C. Using these assay plates, relative amounts of DNA in each well weredetermined using the Cyquant DNA assay kit from R&D Systems (Eugene,Oreg.) following the manufacturer's directions. Results for eachcompound treatment were compared to DMSO vehicle control (100%) and 10μM Actinomycin D treated cells (0%).

Several exemplary compounds useful in the methods of the invention arelisted below. The range of their inhibitory activity against PC-3 cellproliferation is demonstrated, where +++ stands for an IC₅₀ value thatis less than 0.5 μM, ++ between 0.5 and 5 μM, + between 5 and 50 μM.

Compound 70 + Compound 103 ++ Compound 72 ++ Compound 27 +++ Compound74 + Compound 104 +++ Compound 76 ++ Compound 105 + Compound 77 +Compound 106 ++ Compound 81 +++ Compound 108 +++ Compound 82 ++ Compound110 + Compound 84 ++ Compound 112 + Compound 93 ++ Compound 113 +++Compound 94 + Compound 114 +++ Compound 5 ++ Compound 31 +++ Compound53 + Compound 116 +++ Compound 55 ++ Compound 117 +++ Compound 97 +++Compound 121 ++ Compound 98 +++ Compound 123 ++ Compound 99 + Compound124 +++ Compound 100 +++ Compound 127 +++ Compound 19 +++ Compound 129++ Compound 101 ++ Compound 133 + Compound 102 + Compound 136 ++

Example 49 Determination of Affinity for HSP-90 (Heat Shock Protein 90)

Affinity of test compounds for HSP-90 was determined as follows: Proteinmixtures obtained from a variety of organ tissues (for example: spleen,liver and lung) were reversibly bound to a purine affinity column tocapture purine-binding proteins, especially HSP-90. The purine affinitycolumn was washed several times, and then eluted with 20 μM, 100 μM, and500 μM of test compound. Compounds of Formula I elute HP-90 in adose-dependent manner vs. a control elution using dimethylsulfoxide. Theelution profile of Formula I compounds was determined by 1-dimensionalSDS polyacrylamide gel electrophoresis. Gels were stained with afluorescent stain such as sypro ruby (a highly sensitive fluorescentprotein stain that can readily detect less than 1 fmol of total protein,i.e., less than 0.04 ng for a 40 kDa protein) or silver nitrate. Thegels were imaged using a standard flat bed gel imager and the amount ofprotein estimated by densitometry. The percent of HSP-90 protein elutedfrom the column at each concentration was determined and IC₅₀ valueswere calculated from these estimates. The identity of a band containingHSP-90 was determined by protein sequencing using mass spectroscopy.

Compounds of the invention are inhibitors of HSP-90 (heat shock protein90). Several exemplary compounds useful in the methods of the inventionare listed below. The range of their relative binding affinity to HSP-90is demonstrated, where +++ stands for very high, ++ for high and + formoderate.

Compound 30 ++ Compound 55 ++ Compound 70 + Compound 96 +++ Compound73 + Compound 98 +++ Compound 75 +++ Compound 99 ++ Compound 76 +++Compound 102 ++ Compound 77 ++ Compound 103 ++ Compound 78 + Compound105 ++ Compound 79 + Compound 34 ++ Compound 80 + Compound 107 ++Compound 83 +++ Compound 109 ++ Compound 86 ++ Compound 111 +++ Compound87 ++ Compound 115 +++ Compound 88 ++ Compound 32 +++ Compound 91 ++Compound 117 +++ Compound 92 ++ Compound 121 +++ Compound 94 ++ Compound131 ++ Compound 50 +++ Compound 132 +++ Compound 53 ++ Compound 133 ++Compound 95 +++ Compound 134 ++ Compound 54 + Compound 135 +++

The invention and the manner and process of making and using it, are nowdescribed in such full, clear, concise and exact terms as to enable anyperson skilled in the art to which it pertains, to make and use thesame. It is to be understood that the foregoing describes preferredembodiments of the invention and that modifications may be made thereinwithout departing from the spirit or scope of the invention as set forthin the claims. To particularly point out and distinctly claim thesubject matter regarded as invention, the following claims conclude thisspecification.

1.-33. (canceled)
 34. A compound which is4-(6,6-dimethyl-4-oxo-3-trifluoromethyl-4,5,6,7-tetrahydro-indazol-1-yl)-2-(trans-4-hydroxy-cyclohexylamino)-benzamideand has the structure

or a pharmaceutically acceptable salt thereof.
 35. A pharmaceuticalcomposition, comprising a compound according to claim 34, or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier.
 36. A compound which istrans-4-({2-(aminocarbonyl)-5-[6,6-dimethyl-4-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}amino)cyclohexylglycinate and has the structure

or a pharmaceutically acceptable salt thereof.
 37. A pharmaceuticalcomposition, comprising a compound according to claim 36, or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier.